Solid antiviral dosage forms

ABSTRACT

The present disclosure relates to solid dosage forms comprising antiviral compounds and methods of using such dosage forms to treat antiviral infection.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/677,611 filed Apr. 2, 2015, which is incorporated herein by referencein its entirety, and which is a continuation of InternationalApplication No. PCT/US2015/010060 with an international filing date ofJan. 2, 2015, which is incorporated herein by reference in its entirety,and claims priority to U.S. Provisional Application No. 61/976,934 filedApr. 8, 2014, and U.S. Provisional Application No. 61/923,544 filed Jan.3, 2014, both of which are incorporated herein by reference in theirentirety.

FIELD OF THE INVENTION

The present disclosure relates to solid dosage forms comprisingantiviral compounds, methods of preparing the solid dosage forms, andmethods of using such dosage forms to treat antiviral infection.

BACKGROUND OF THE INVENTION

Hepatitis C virus (“HCV”) infection is associated with progressive liverpathology, including cirrhosis and hepatocellular carcinoma. Standard ofcare for treating chronic HCV infection generally comprisesadministration of peginterferon-alpha in combination with ribavirin tothe patient. Treatment often additionally comprises administering ahepatitis C protease inhibitor to genotype 1-infected patients. Manypatients, however, suffer side effects from the treatment, and viralelimination from the body is often inadequate. In view of the limitedefficacy and tolerability of such standard of care treatment, thereremains a need for new drugs to treat HCV infection.

BRIEF DESCRIPTION OF THE INVENTION

The present disclosure relates to solid dosage forms comprising Compound1, Compound 2, Compound 3, and Compound 4 (as those compounds aredefined in the disclosure below).

In an aspect, the present disclosure relates to solid dosage formscomprising Compound 1, Compound 2, and Compound 3 in a firstcomposition, and Compound 4 in a second composition.

In one aspect, the present disclosure relates to solid dosage formscomprising Compound 1, Compound 2, Compound 3, and Compound 4, whereinthe weight ratio (free acid or free base) of Compound 1:Compound2:Compound 3 is from 10:1:2 to 2:1:3.

In another aspect, the disclosure relates to solid dosage formscomprising:

-   -   (a) 40 mg to 180 mg (free acid equivalent weight) of Compound 1;    -   (b) 5 mg to 30 mg (free base equivalent weight) of Compound 2;    -   (c) 25 mg to 120 mg (free base equivalent weight) of Compound 3;        and    -   (d) 75 mg to 900 mg (free acid equivalent weight) of Compound 4.

In another aspect, the disclosure relates to solid dosage formscomprising:

-   -   (a) a first composition comprising:        -   (i) 40 mg to 90 mg (free acid equivalent weight) of Compound            1;        -   (ii) 5 mg to 15 mg (free base equivalent weight) of Compound            2; and        -   (iii) 25 mg to 60 mg (free base equivalent weight) of            Compound 3; and    -   (b) a second composition comprising:        -   (i) 75 mg to 450 mg (free acid equivalent weight) of            Compound 4;        -   (ii) a pharmaceutically acceptable stabilizing polymer, or            combination of pharmaceutically acceptable stabilizing            polymers, in an amount of at least 5% by weight of the            second composition; and        -   (iii) a pharmaceutically acceptable release rate-modifying            polymer, or combination of pharmaceutically acceptable            release rate-modifying polymers, in an amount of at least 5%            by weight of the second composition;        -   wherein the stabilizing polymer, or combination of            stabilizing polymers, and the release rate-modifying            polymer, or combination of release rate-modifying polymers,            can be the same or different.

In another aspect, the disclosure relates to methods for treating HCVinfection in a subject in need of such treatment, wherein the methodscomprise administering at least one dosage form of the presentdisclosure once daily to the subject. In one aspect, the methodscomprise administering two dosage forms of the present disclosure oncedaily to the subject. In another aspect, the methods compriseadministering three dosage forms of the present disclosure once daily tothe subject.

In another aspect, the disclosure relates to methods for treating liverdisease in a subject in need of such treatment, wherein the methodscomprise administering at least one dosage form of the presentdisclosure once daily to the subject. In one aspect, the methodscomprise administering two dosage forms of the present disclosure oncedaily to the subject. In another aspect, the methods compriseadministering three dosage forms of the present disclosure once daily tothe subject.

In another aspect, the disclosure relates to kits comprising one or moreof the dosage forms of the present disclosure.

In another aspect, the disclosure relates to processes for making thedosage forms of the present disclosure, wherein the processes comprise:

-   -   (a) preparing a melt comprising Compound 1, Compound 2, Compound        3, a hydrophilic polymer, and a surfactant;    -   (b) solidifying the melt to provide an amorphous solid        dispersion;    -   (c) preparing a first composition comprising the amorphous solid        dispersion;    -   (d) preparing a second composition comprising Compound 4 and a        pharmaceutically acceptable stabilizing polymer, or combination        of pharmaceutically acceptable stabilizing polymers; and    -   (e) formulating the first composition and the second composition        to provide the dosage form.

In another aspect, the disclosure relates to solid dosage forms preparedin accordance with the above processes.

DETAILED DESCRIPTION OF THE INVENTION

This written description uses examples to illustrate the invention andalso to enable any person skilled in the art to practice the invention,including making and using any compositions and performing any relatedmethods. The patentable scope of the invention is defined by the claims,and may include other examples that occur to those skilled in the art.Such other examples are intended to be within the scope of the claims ifthey have structural elements that do not differ from the literallanguage of the claims or if they include equivalent structural elementswith insubstantial differences from the literal language of the claims.

I. DEFINITIONS

Section headings as used in this section and the entire disclosure arenot intended to be limiting.

Where a numeric range is recited, each intervening number within therange is explicitly contemplated with the same degree of precision. Forexample, for the range 6 to 9, the numbers 7 and 8 are contemplated inaddition to 6 and 9, and for the range 6.0-7.0, the numbers 6.0, 6.1,6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9 and 7.0 are explicitlycontemplated. In the same manner, all recited ratios also include allsub-ratios falling within the broader ratio.

The term “AUC_(∞)” refers to the area under the plasmaconcentration-time curve from the time 0 (time of dosing) to infinity(∞), as calculated by the linear trapezoidal method.

The term “C_(max)” refers to the maximum observed plasma concentrationover the entire sampling period.

The term “C₂₄” refers to the plasma concentration at 24 hours.

The term “particle size” refers to particle size as measured byconventional particle size measuring techniques such as laser lightscattering. The term “D₁₀ particle size” means the particle sizedistribution of at least 10% of the particles as measured by laser lightscattering particle size measuring techniques. The term “D₅₀ particlesize” means the particle size distribution of at least 50% of theparticles as measured by laser light scattering particle size measuringtechniques. The term “D₉₀ particle size” means the particle sizedistribution of at least 90% of the particles as measured by laser lightscattering particle size measuring techniques.

The term “subject” refers to a human subject.

The term “T_(max)” refers to the time of the maximum observed plasmaconcentration (C_(max)).

The abbreviation “cTAB” means cetyltrimethylammonium bromide.

The abbreviation “FeSSIF” means Fed-State Simulated Intestinal Fluid.

The abbreviation “HCV” means hepatitis C virus.

The abbreviation “HLB” means Hydrophobic-Lipophilic Balance.

The abbreviation “HPMC” means hydroxypropyl methylcellulose.

The abbreviation “PXRD” means powder X-ray diffraction.

The abbreviation “T_(g)” means glass transition temperature.

The abbreviation “v/v” refers to volume/volume.

The abbreviation “w/v” refers to weight/volume.

The abbreviation “w/w” refers to weight/weight.

II. SOLID DOSAGE FORMS

Combination therapy treatment of HCV-infected adult human subjectscomprising the administration to those subjects of Compound 1, Compound2, Compound 3, and Compound 4 (which are further described below) wasevaluated in Phase III clinical trials. The Phase III trials employedtwo separate dosage forms, a first tablet comprising Compound 1,Compound 2, and Compound 3 (the “Triple Tablet”), and a second tabletcomprising Compound 4 as the only active ingredient (the “SingleTablet”). The daily dosing regimen under evaluation in the Phase IIIclinical trials has required administration to the subject of two TripleTablets and one Single Tablet in the morning and the administration ofone Single Tablet to the subject in the evening. Initial results haveindicated that such combination therapy treatment is effective.

A. Active Ingredients

Compound 1:

The compound(2R,6S,13aS,14aR,16aS,Z)—N-(cyclopropylsulfonyl)-6-(5-methylpyrazine-2-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxamide(also known as ABT-450 or paritaprevir) is an HCV protease inhibitor andhas the structure shown below:

For convenience, this compound and its pharmaceutically acceptable saltsare collectively referred to as Compound 1 throughout this disclosure.The synthesis and formulation of Compound 1 are described, for example,in U.S. Patent Application Publication Nos. 2010/0144608 and2011/0312973.

Compound 2:

The compound dimethyl(2S,2′S)-1,1′-((2S,2′S)-2,2′-(4,4′-((2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl)bis(4,1-phenylene))bis(azanediyl)bis-(oxomethylene)bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl)-dicarbamate(also known as ABT-267 or ombitasvir) is an HCV NS5A inhibitor and hasthe structure shown below:

For convenience, this compound and its pharmaceutically acceptable saltsare collectively referred to as Compound 2 throughout this disclosure.The synthesis and formulation of Compound 2 are described, for example,in U.S. Patent Application Publication Nos. 2010/0317568 and2012/0258909.

Compound 3: The compound 1,3-thiazol-5-ylmethylN-[(2S,3S,5S)-3-hydroxy-5-[(2S)-3-methyl-2-{[methyl({[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl})carbamoyl]-amino}butanamido]-1,6-diphenylhexan-2-yl]carbamate(also known as ritonavir) is a protease inhibitor and has the structureshown below:

For convenience, this compound and its pharmaceutically acceptable saltsare collectively referred to as Compound 3 throughout this disclosure.The synthesis and formulation of Compound 3 are described, for example,in U.S. Pat. No. 5,541,206 and U.S. Pat. No. 8,268,349. Compound 3 isthe active ingredient in the commercially available product NORVIR®.

Compound 4:

The compoundN-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide(also known as ABT-333 or dasabuvir) is a polymerase inhibitor and hasthe structure shown below:

For convenience, this compound and its pharmaceutically acceptable saltsare collectively referred to as Compound 4 throughout this disclosure.The synthesis and formulation of Compound 4 are described, for example,in International Application Publication WO2009/039134.

Unless otherwise stated, any reference in this disclosure to an amountof Compound 1, Compound 2, Compound 3, or Compound 4 is intended torefer to the free acid or free base equivalent weight of the compound.For example, 350 mg of Compound 4 refers to 350 mg of the free acid ofCompound 4 or an equivalent amount of a salt (e.g., a sodium salt) ofCompound 4.

The present disclosure relates, in part, to one or more solid dosageforms that comprise all four of the active ingredients (Compound 1,Compound 2, Compound 3, and Compound 4) employed in the combinationtherapy evaluated in Phase III clinical trials discussed above. Suchsolid dosage forms, inter alia, can be administered to the subjectpursuant to a once-daily dosing regimen, provide substantiallycomparable efficacy relative to, and are preferably bioequivalent to,the Triple Tablet/Single Tablet dosing regimen, and/or result inimproved patient compliance. However, co-formulation of all four activeingredients in a single solid dosage form has been challenging in viewof a number of factors, including the following:

(a) Total Daily Dose:

The combined daily dose of Compound 1 (150 mg), Compound 2 (25 mg),Compound 3 (100 mg), and Compound 4 (500 mg) administered to the subjectin Phase III clinical trials is relatively large, totaling 775 mg andmust be administered in four tablets.

(b) Dosage Form Size:

The Triple Tablet (1117 mg) and Single Tablet (697 mg) administered tosubjects in Phase III clinical trials are large in size.

(c) Drug Loading:

Drug loading limitations previously impacted the development of theTriple Tablet. Consolidating the four active ingredients into a singledosage form only exacerbates that problem.

-   -   (d) Different Pharmacokinetic Profiles:

The daily dosing regimen for the Triple Tablet (once-daily dosingregimen) and the Single Tablet (twice-daily dosing regimen) differ, anddeliver a specific pharmacokinetic profile for each of the fourcompounds.

-   -   (e) Solubility:

Compound 1, Compound 2, Compound 3, and Compound 4 have low solubility.They generally exhibit lower bioavailability and/or higher variabilityin bioavailability relative to more soluble compounds due to their pooraqueous solubility and low dissolution.

(f) Free Acid Conversion (Compound 4):

The free acid of Compound 4 exhibits good permeability but poorsolubility in the gastrointestinal tract. Administering a salt ofCompound 4 (such as the sodium salt) rather than the free acid form ofCompound 4, however, does not improve Compound 4 solubility and uptakein the gastrointestinal tract to the extent expected due to unknownreasons.

(g) Regional Absorption (Compound 4):

The rate and extent of Compound 4 absorption varies throughout thegastrointestinal tract, making it difficult to design a once dailydosing that is bioequivalent to twice daily dosing.

Individually, the above considerations present significant challenges toco-formulating all four active ingredients in a suitable solid dosageform. Collectively, these considerations further increase the difficultyof co-formulating all four active ingredients in a suitable solid dosageform without adversely impacting dosage form size and/or the number ofunit dosage forms that must be administered on a daily basis whileachieving suitable efficacy and bioavailability.

B. Therapeutic Dose and Regimen

The dosage forms of the present invention are administered in accordancewith a daily dosing regimen that orally delivers a therapeutic amount ofCompounds 1, 2, 3, and 4 to a subject. This daily dosing regimengenerally delivers an amount of Compounds 1, 2, 3, and 4 within theranges set forth in Table A below.

TABLE A Daily Therapeutic Dose ACTIVE INGREDIENT DAILY THERAPEUTIC DOSE(mg) Compound 1 80 to 180 (e.g., 150) Compound 2 10 to 30 (e.g., 25)Compound 3 50 to 120 (e.g., 100) Compound 4 450 to 900 (e.g., 500 or600)Due to drug loading limitations and dosage form size constraints,administration of two or more of the dosage forms of the presentinvention typically will be required to deliver the necessary dailytherapeutic dose to the subject. In one aspect, daily administration oftwo of the dosage forms will provide the necessary daily therapeuticdose to the subject. In another aspect, daily administration of three ofthe dosage forms will provide the necessary daily therapeutic dose tothe subject. If desired, however, daily administration of four or moreof the dosage forms can be employed to provide the necessary dailytherapeutic dose to the subject.

C. Dosage Form Illustrative Embodiments

The present disclosure relates, in part, to a solid dosage formcomprising:

-   -   (a) 40 mg to 180 mg (free acid equivalent weight) of Compound 1,        wherein Compound 1 is:

or a pharmaceutically acceptable salt thereof;

-   -   (b) 5 mg to 30 mg (free base equivalent weight) of Compound 2,        wherein Compound 2 is:

or a pharmaceutically acceptable salt thereof;

-   -   (c) 25 mg to 120 mg (free base equivalent weight) of Compound 3,        wherein Compound 3 is ritonavir, or a pharmaceutically        acceptable salt thereof; and    -   (d) 75 mg to 900 mg (free acid equivalent weight) of Compound 4,        wherein Compound 4 is:

or a pharmaceutically acceptable salt thereof.

The dosage form generally will comprise Compounds 1, 2, and 3 at aweight ratio (free acid or free base) of 3:2:24 to 60:3:5 (Compound1:Compound 2:Compound 3). In one aspect, the weight ratio is 10:1:2 to2:1:3 (Compound 1:Compound 2:Compound 3). In another aspect, the weightratio is 6:1:4 (Compound 1:Compound 2:Compound 3).

Suitable dosage forms (e.g., tablets, capsules, sachets, etc.) andrepresentative examples of such dosage form types are discussed ingreater detail in Section II.J below.

As mentioned above, the dosage forms of the present disclosure may beadministered pursuant to a daily dosing regimen that comprises, forexample, either administering two of the dosage forms daily to thesubject or administering three of the dosage forms daily to the subject.In one aspect, the two or three dosage forms are administered to thesubject substantially simultaneously each day. In one aspect, the two orthree dosage forms are administered to the subject substantiallysequentially each day. Representative embodiments of dosage forms thatcan be employed in each regimen are set forth below.

In one embodiment, the dosage forms comprises:

-   -   (a) 40 mg to 90 mg (free acid equivalent weight) of Compound 1;    -   (b) 5 mg to 15 mg (free base equivalent weight) of Compound 2;    -   (c) 25 mg to 60 mg (free base equivalent weight) of Compound 3;        and    -   (d) 75 mg to 450 mg (free acid equivalent weight) of Compound 4.

In another embodiment, the dosage form comprises:

-   -   (a) a first composition comprising:        -   (i) 40 mg to 90 mg (free acid equivalent weight) of Compound            1;        -   (ii) 5 mg to 15 mg (free base equivalent weight) of Compound            2; and        -   (iii) 25 mg to 60 mg (free base equivalent weight) of            Compound 3; and    -   (b) a second composition comprising:        -   (i) 75 mg to 450 mg (free acid equivalent weight) of            Compound 4;        -   (ii) a pharmaceutically acceptable stabilizing polymer, or            combination of pharmaceutically acceptable stabilizing            polymers, in an amount of at least 5% by weight of the            second composition; and        -   (iii) a pharmaceutically acceptable release rate-modifying            polymer, or combination of pharmaceutically acceptable            release rate-modifying polymers, in an amount of at least 5%            by weight of the second composition;        -   wherein the stabilizing polymer, or combination of            stabilizing polymers, and the release rate-modifying            polymer, or combination of release rate-modifying polymers,            can be the same or different.

The first composition may further comprise a portion of the total amountof Compound 4 present in the dosage form. The amount of Compound 4present in the first composition may not exceed the amount of Compound 4present in the second composition. In one aspect, the amount of Compound4 present in the first composition is less than or equal to 45% of theamount of Compound 4 present in the dosage form. In another aspect, theamount of Compound 4 present in the first composition is less than orequal to 40% of the amount of Compound 4 present in the dosage form. Inanother aspect, the amount of Compound 4 present in the firstcomposition is less than or equal to 35% of the amount of Compound 4present in the dosage form. In another aspect, the amount of Compound 4present in the first composition is less than or equal to 30% of theamount of Compound 4 present in the dosage form. In another aspect, theamount of Compound 4 present in the first composition is less than orequal to 25% of the amount of Compound 4 present in the dosage form. Inanother aspect, the amount of Compound 4 present in the firstcomposition is less than or equal to 20% of the amount of Compound 4present in the dosage form. In another aspect, the amount of Compound 4present in the first composition is less than or equal to 15% of theamount of Compound 4 present in the dosage form. In another aspect, theamount of Compound 4 present in the first composition is 25% of theamount of Compound 4 present in the dosage form.

In another embodiment of the dosage form:

-   -   the first composition comprises (i) 60 mg to 90 mg (free acid        equivalent weight) of Compound 1; (ii) 10 mg to 15 mg (free base        equivalent weight) of Compound 2; and (iii) 40 mg to 60 mg (free        base equivalent weight) of Compound 3; and the second        composition comprises 225 mg to 450 mg (free acid equivalent        weight) of Compound 4.

In another embodiment of the dosage form:

-   -   the first composition comprises (i) 70 mg to 80 mg (free acid        equivalent weight) of Compound 1; (ii) 11 mg to 14 mg (free base        equivalent weight) of Compound 2; and (iii) 45 mg to 55 mg (free        base equivalent weight) of Compound 3; and    -   the second composition comprises 225 mg to 400 mg (free acid        equivalent weight) of Compound 4.

In another embodiment of the dosage form:

-   -   the first composition comprises (i) 75 mg (free acid equivalent        weight) of Compound 1; (ii) 12.5 mg (free base equivalent        weight) of Compound 2; and (iii) 50 mg (free base equivalent        weight) of Compound 3; and    -   the second composition comprises 300 mg to 400 mg (free acid        equivalent weight) of Compound 4.

In another embodiment of the dosage form:

-   -   the first composition comprises (i) 75 mg (free acid equivalent        weight) of Compound 1; (ii) 12.5 mg (free base equivalent        weight) of Compound 2; and (iii) 50 mg (free base equivalent        weight) of Compound 3; and    -   the second composition comprises 300 mg to 400 mg (free acid        equivalent weight) of Compound 4; and    -   the stabilizing polymer comprises copovidone.

In another embodiment of the dosage form:

-   -   the first composition comprises (i) 75 mg (free acid equivalent        weight) of Compound 1; (ii) 12.5 mg (free base equivalent        weight) of Compound 2; and (iii) 50 mg (free base equivalent        weight) of Compound 3; and    -   the second composition comprises 300 mg to 400 mg (free acid        equivalent weight) of Compound 4;    -   the stabilizing polymer comprises copovidone; and    -   the release rate-modifying polymer comprises hydroxypropyl        methylcellulose.

In another embodiment of the dosage form:

-   -   the first composition comprises (i) 60 mg to 90 mg (free acid        equivalent weight) of Compound 1; (ii) 10 mg to 15 mg (free base        equivalent weight) of Compound 2; and (iii) 40 mg to 60 mg (free        base equivalent weight) of Compound 3; and    -   the first composition further comprises 25 mg to 225 mg (free        acid equivalent weight) of Compound 4;    -   wherein the dosage form comprises a total amount of Compound 4        (free acid equivalent weight) from 225 mg to 450 mg; and    -   the amount of Compound 4 (free acid equivalent weight) in the        first composition is less than or equal to the amount of        Compound 4 (free acid equivalent weight) in the second        composition.

In another embodiment of the dosage form:

-   -   the first composition comprises (i) 70 mg to 80 mg (free acid        equivalent weight) of Compound 1; (ii) 11 mg to 14 mg (free base        equivalent weight) of Compound 2; and (iii) 45 mg to 55 mg (free        base equivalent weight) of Compound 3; and    -   the first composition further comprises 25 mg to 225 mg (free        acid equivalent weight) of Compound 4;    -   wherein the dosage form comprises a total amount of Compound 4        (free acid equivalent weight) from 225 mg to 450 mg; and    -   the amount of Compound 4 (free acid equivalent weight) in the        first composition is less than or equal to the amount of        Compound 4 (free acid equivalent weight) in the second        composition.

In another embodiment of the dosage form:

-   -   the first composition comprises (i) 75 mg (free acid equivalent        weight) of Compound 1; (ii) 12.5 mg (free base equivalent        weight) of Compound 2; and (iii) 50 mg (free base equivalent        weight) of Compound 3; and    -   the first composition further comprises 25 mg to 200 mg (free        acid equivalent weight) of Compound 4;    -   wherein the dosage form comprises a total amount of Compound 4        (free acid equivalent weight) from 300 mg to 400 mg; and    -   the amount of Compound 4 (free acid equivalent weight) in the        first composition is less than or equal to the amount of        Compound 4 (free acid equivalent weight) in the second        composition.

In another embodiment of the dosage form:

-   -   the first composition comprises (i) 75 mg (free acid equivalent        weight) of Compound 1; (ii) 12.5 mg (free base equivalent        weight) of Compound 2; and (iii) 50 mg (free base equivalent        weight) of Compound 3; and    -   the first composition further comprises 25 mg to 200 mg (free        acid equivalent weight) of Compound 4;    -   wherein the dosage form comprises a total amount of Compound 4        (free acid equivalent weight) from 300 mg to 400 mg;    -   the amount of Compound 4 (free acid equivalent weight) in the        first composition is less than or equal to the amount of        Compound 4 (free acid equivalent weight) in the second        composition; and    -   the stabilizing polymer comprises copovidone.

In another embodiment of the dosage form:

-   -   the first composition comprises (i) 75 mg (free acid equivalent        weight) of Compound 1; (ii) 12.5 mg (free base equivalent        weight) of Compound 2; and (iii) 50 mg (free base equivalent        weight) of Compound 3; and    -   the first composition further comprises 25 mg to 200 mg (free        acid equivalent weight) of Compound 4;    -   wherein the dosage form comprises a total amount of Compound 4        (free acid equivalent weight) from 300 mg to 400 mg;    -   the amount of Compound 4 (free acid equivalent weight) in the        first composition is less than or equal to the amount of        Compound 4 (free acid equivalent weight) in the second        composition;    -   the stabilizing polymer comprises copovidone; and    -   the release rate-modifying polymer comprises hydroxypropyl        methylcellulose.

In another embodiment of the dosage form:

-   -   the first composition comprises (i) 40 mg to 60 mg (free acid        equivalent weight) of Compound 1; (ii) 6.5 mg to 10.5 mg (free        base equivalent weight) of Compound 2; and (iii) 25 mg to 40 mg        (free base equivalent weight) of Compound 3; and    -   the second composition comprises 150 mg to 300 mg (free acid        equivalent weight) of Compound 4.

In another embodiment of the dosage form:

-   -   the first composition comprises (i) 45 mg to 55 mg (free acid        equivalent weight) of Compound 1; (ii) 7.5 mg to 9.5 mg (free        base equivalent weight) of Compound 2; and (iii) 30 mg to 37 mg        (free base equivalent weight) of Compound 3; and    -   the second composition comprises 150 mg to 300 mg (free acid        equivalent weight) of Compound 4.

In another embodiment of the dosage form:

-   -   the first composition comprises (i) 50 mg (free acid equivalent        weight) of Compound 1; (ii) 8.3 mg (free base equivalent weight)        of Compound 2; and (iii) 33.3 mg (free base equivalent weight)        of Compound 3; and    -   the second composition comprises 190 mg to 250 mg (free acid        equivalent weight) of Compound 4.

In another embodiment of the dosage form:

-   -   the first composition comprises (i) 50 mg (free acid equivalent        weight) of Compound 1; (ii) 8.3 mg (free base equivalent weight)        of Compound 2; and (iii) 33.3 mg (free base equivalent weight)        of Compound 3; and    -   the second composition comprises 190 mg to 250 mg (free acid        equivalent weight) of Compound 4; and    -   the stabilizing polymer comprises copovidone.

In another embodiment of the dosage form:

-   -   the first composition comprises (i) 50 mg (free acid equivalent        weight) of Compound 1; (ii) 8.3 mg (free base equivalent weight)        of Compound 2; and (iii) 33.3 mg (free base equivalent weight)        of Compound 3; and    -   the second composition comprises 190 mg to 250 mg (free acid        equivalent weight) of Compound 4;    -   the stabilizing polymer comprises copovidone; and    -   the release rate-modifying polymer comprises hydroxypropyl        methylcellulose.

In another embodiment of the dosage form:

-   -   the first composition comprises (i) 40 mg to 60 mg (free acid        equivalent weight) of Compound 1; (ii) 6.5 mg to 10.5 mg (free        base equivalent weight) of Compound 2; and (iii) 25 mg to 40 mg        (free base equivalent weight) of Compound 3; and    -   the first composition further comprises 25 mg to 150 mg (free        acid equivalent weight) of Compound 4;    -   wherein the dosage form comprises a total amount of Compound 4        (free acid equivalent weight) from 150 mg to 300 mg; and    -   the amount of Compound 4 (free acid equivalent weight) in the        first composition is less than or equal to the amount of        Compound 4 (free acid equivalent weight) in the second        composition.

In another embodiment of the dosage form:

-   -   the first composition comprises (i) 45 mg to 55 mg (free acid        equivalent weight) of Compound 1; (ii) 7.5 mg to 9.5 mg (free        base equivalent weight) of Compound 2; and (iii) 30 mg to 37 mg        (free base equivalent weight) of Compound 3; and    -   the first composition further comprises 25 mg to 150 mg (free        acid equivalent weight) of Compound 4;    -   wherein the dosage form comprises a total amount of Compound 4        (free acid equivalent weight) from 150 mg to 300 mg; and    -   the amount of Compound 4 (free acid equivalent weight) in the        first composition is less than or equal to the amount of        Compound 4 (free acid equivalent weight) in the second        composition.

In another embodiment of the dosage form:

-   -   the first composition comprises (i) 50 mg (free acid equivalent        weight) of Compound 1; (ii) 8.3 mg (free base equivalent weight)        of Compound 2; and (iii) 33.3 mg (free base equivalent weight)        of Compound 3; and    -   the first composition further comprises 25 mg to 135 mg (free        acid equivalent weight) of Compound 4;    -   wherein the dosage form comprises a total amount of Compound 4        (free acid equivalent weight) from 190 mg to 250 mg; and    -   the amount of Compound 4 (free acid equivalent weight) in the        first composition is less than or equal to the amount of        Compound 4 (free acid equivalent weight) in the second        composition.

In another embodiment of the dosage form:

-   -   the first composition comprises (i) 50 mg (free acid equivalent        weight) of Compound 1; (ii) 8.3 mg (free base equivalent weight)        of Compound 2; and (iii) 33.3 mg (free base equivalent weight)        of Compound 3; and    -   the first composition further comprises 25 mg to 135 mg (free        acid equivalent weight) of Compound 4;    -   wherein the dosage form comprises a total amount of Compound 4        (free acid equivalent weight) from 190 mg to 250 mg;    -   the amount of Compound 4 (free acid equivalent weight) in the        first composition is less than or equal to the amount of        Compound 4 (free acid equivalent weight) in the second        composition; and    -   the stabilizing polymer comprises copovidone.

In another embodiment of the dosage form:

-   -   the first composition comprises (i) 50 mg (free acid equivalent        weight) of Compound 1; (ii) 8.3 mg (free base equivalent weight)        of Compound 2; and (iii) 33.3 mg (free base equivalent weight)        of Compound 3; and    -   the first composition further comprises 25 mg to 135 mg (free        acid equivalent weight) of Compound 4;    -   wherein the dosage form comprises a total amount of Compound 4        (free acid equivalent weight) from 190 mg to 250 mg;    -   the amount of Compound 4 (free acid equivalent weight) in the        first composition is less than or equal to the amount of        Compound 4 (free acid equivalent weight) in the second        composition;    -   the stabilizing polymer comprises copovidone; and    -   the release rate-modifying polymer comprises hydroxypropyl        methylcellulose.

D. Compound 4

The dosage form typically will comprise a pharmaceutically acceptablesalt of Compound 4. In one aspect, the salt is an alkali metal salt. Inanother aspect, the salt is a sodium salt. In another aspect, the saltis a crystalline salt. In another aspect, the salt is a pattern Bcrystalline monosodium salt having an X-ray powder diffraction patterncomprising one or more peaks selected from the group consisting of5.4±0.2, 10.8±0.2, 14.4±0.2, 16.3±0.2, 17.0±0.2, 21.6±0.2, 22.1±0.2, and23.7±0.2 degrees two theta when measured at 25° C. with monochromaticCu—K_(α)1 radiation; or an X-ray powder diffraction pattern comprisingone or more peaks selected from the group consisting of 5.4±0.2,10.8±0.2, 14.4±0.2, 16.3±0.2, 17.0±0.2, 18.8±0.2, 19.2±0.2, 19.6±0.2,21.6±0.2, 22.1±0.2, 23.7±0.2, 28.8±0.2, 29.1±0.2, and 31.8±0.2 degreestwo theta when measured at 25° C. with monochromatic Cu—K_(α)1radiation; or an X-ray powder diffraction pattern comprising three ormore peaks selected from the group consisting of 5.4±0.2, 10.8±0.2,16.3±0.2, 22.1±0.2, and 23.7±0.2 degrees two theta when measured at 25°C. with monochromatic Cu—K_(α)1 radiation; or an X-ray powderdiffraction pattern comprising peaks at 5.4±0.2, 10.8±0.2, 16.3±0.2, and22.1±0.2 degrees two theta when measured at 25° C. with monochromaticCu—K_(α)1 radiation. In another aspect, the pattern B monosodium salt isa pattern B monosodium salt monohydrate. In another aspect, the salt isan amorphous salt. In another aspect, the salt is an amorphousmonosodium salt.

The amount of Compound 4 (free acid equivalent weight) in the secondcomposition generally is at least 20% by weight of the secondcomposition. In one aspect, the amount of Compound 4 (free acidequivalent weight) in the second composition is at least 25% by weightof the second composition. In another aspect, the amount of Compound 4(free acid equivalent weight) in the second composition is at least 30%by weight of the second composition. In another aspect, the amount ofCompound 4 (free acid equivalent weight) in the second composition is atleast 35% by weight of the second composition. In another aspect, theamount of Compound 4 (free acid equivalent weight) in the secondcomposition is at least 40% by weight of the second composition. Inanother aspect, the amount of Compound 4 (free acid equivalent weight)in the second composition is 20% to 60% percent by weight of the secondcomposition. In another aspect, the amount of Compound 4 (free acidequivalent weight) in the second composition is 25% to 55% percent byweight of the second composition. In another aspect, the amount ofCompound 4 (free acid equivalent weight) in the second composition is35% to 50% percent by weight of the second composition.

E. Stabilizing Polymer

The amount of the stabilizing polymer, or combination of stabilizingpolymers, in the second composition generally is at least 5% by weightof the second composition. In one aspect, the amount of the stabilizingpolymer, or combination of stabilizing polymers, in the secondcomposition is at least 10% by weight. In another aspect, the amount ofthe stabilizing polymer, or combination of stabilizing polymers, in thesecond composition is at least 15% by weight. In another aspect, theamount of the stabilizing polymer, or combination of stabilizingpolymers, in the second composition is at least 20% by weight. Inanother aspect, the amount of the stabilizing polymer, or combination ofstabilizing polymers, in the second composition is at least 25% byweight. In another aspect, the amount of the stabilizing polymer, orcombination of stabilizing polymers, in the second composition is atleast 30% by weight. In another aspect, the amount of the stabilizingpolymer, or combination of stabilizing polymers, in the secondcomposition is 10% to 60% percent by weight. In another aspect, theamount of the stabilizing polymer, or combination of stabilizingpolymers, in the second composition is 15% to 55% percent by weight. Inanother aspect, the amount of the stabilizing polymer, or combination ofstabilizing polymers, in the second composition is 20% to 50% percent byweight. In another aspect, the amount of the stabilizing polymer, orcombination of stabilizing polymers, in the second composition is 25% to45% percent by weight. In another aspect, the amount of the stabilizingpolymer, or combination of stabilizing polymers, in the secondcomposition is 25% to 40% percent by weight.

In one embodiment, the weight ratio of the stabilizing polymer, orcombination of stabilizing polymers, to Compound 4 (free acid equivalentweight) in the second composition is from 4:1 to 1:8. In one aspect, theweight ratio of the stabilizing polymer, or combination of stabilizingpolymers, to Compound 4 (free acid equivalent weight) in the secondcomposition is 2:1 to 1:4. In another aspect, the weight ratio of thestabilizing polymer, or combination of stabilizing polymers, to Compound4 (free acid equivalent weight) in the second composition is 1:1 to1:3.5. In another aspect, the weight ratio of the stabilizing polymer,or combination of stabilizing polymers, to Compound 4 (free acidequivalent weight) in the second composition is 1:1.5 to 1:3.5. Inanother aspect, the weight ratio of the stabilizing polymer, orcombination of stabilizing polymers, to Compound 4 (free acid equivalentweight) in the second composition is 1:2 to 1:3.

When Compound 4 is present in both the first composition and the secondcomposition of the dosage form, the first composition may furthercomprise a stabilizing polymer, or combination of stabilizing polymers,in the same manner as previously described for the second composition.In such dosage forms, the weight ratio of the stabilizing polymer, orcombination of stabilizing polymers, to Compound 4 (free acid equivalentweight) in the first composition is from 4:1 to 1:8, or as otherwisedescribed above for the various aspects of the second composition.

The stabilizing polymer, or combination of stabilizing polymers,selected generally will inhibit precipitation of Compound 4. In oneaspect, the stabilizing polymer, or combination of stabilizing polymers,inhibits precipitation of Compound 4 by at least 10% to 80% relative toa substantially identical dosage form that does not contain thestabilizing polymer, or combination of stabilizing polymers. In oneaspect, the stabilizing polymer, or combination of stabilizing polymers,inhibits precipitation of Compound 4 by at least 10% relative to asubstantially identical dosage form that does not contain thestabilizing polymer, or combination of stabilizing polymers. In anotheraspect, the stabilizing polymer, or combination of stabilizing polymers,inhibits precipitation of Compound 4 by at least 20%. In another aspect,the stabilizing polymer, or combination of stabilizing polymers,inhibits precipitation of Compound 4 by at least 30%. In another aspect,the stabilizing polymer, or combination of stabilizing polymers,inhibits precipitation of Compound 4 by at least 40%. In another aspect,the stabilizing polymer, or combination of stabilizing polymers,inhibits precipitation of Compound 4 by at least 50%. In another aspect,the stabilizing polymer, or combination of stabilizing polymers,inhibits precipitation of Compound 4 by at least 60%. In another aspect,the stabilizing polymer, or combination of stabilizing polymers,inhibits precipitation of Compound 4 by at least 70%. In another aspect,the stabilizing polymer, or combination of stabilizing polymers,inhibits precipitation of Compound 4 by at least 80%.

In one embodiment, the stabilizing polymer, or combination ofstabilizing polymers, selected for the dosage form inhibitsprecipitation of Compound 4 as determined by the process comprising:

-   -   (a) preparing a test solution comprising Compound 4, or a salt        thereof, and the stabilizing polymer, or combination of        stabilizing polymers;    -   (b) preparing a control solution, the control solution being        substantially identical to the test solution except that the        control solution does not contain the stabilizing polymer, or        combination of stabilizing polymers;    -   (c) maintaining the test mixture and the control solution under        the same conditions for a test period; and    -   (d) determining at the end of the test period the extent to        which precipitation of Compound 4, or a salt thereof, is        inhibited in the test solution relative to the control solution.

Suitable methods for determining whether precipitation of Compound 4 hasbeen inhibited in the test solution relative to the control solutioninclude UV/Vis spectrophotometry using an in situ UV/Vis probe; HPLCassay of the supernatant solution after removing particles; and otherconventional methods known to those of skill in the art.

In one aspect, the stabilizing polymer, or combination of stabilizingpolymers, inhibits precipitation of Compound 4 by at least 10% to 80%relative to a substantially identical dosage form that does not containthe stabilizing polymer, or combination of stabilizing polymers, asdetermined by the process comprising: (a) preparing a test solutioncomprising Compound 4, or a salt thereof, and the stabilizing polymer,or combination of stabilizing polymers; (b) preparing a controlsolution, the control solution being substantially identical to the testsolution except that the control solution does not contain thestabilizing polymer, or combination of stabilizing polymers; (c)maintaining the test mixture and the control solution under the sameconditions for a test period; and (d) determining at the end of the testperiod the extent to which precipitation of Compound 4, or a saltthereof, is inhibited in the test solution relative to the controlsolution by UV/Vis spectrophotometry using an in situ UV/Vis probe.

It is hypothesized that in dosage forms comprising a salt of Compound 4but lacking a sufficient amount of the stabilizing polymer, orcombination of stabilizing polymers, the salt is rapidly converted tothe relatively insoluble free acid when the salt comes into contact withthe acidic environment of the stomach. The free acid then precipitateson the surface of the solid dosage form without being released into thesurrounding medium and/or precipitates out of the surrounding medium.This precipitation of the free acid results in a smaller amount of theadministered dose of Compound 4 dissolving in the medium and beingavailable for uptake and lowers the overall bioavailability of Compound4. It is further hypothesized that the incorporation of the stabilizingpolymer, or combination of stabilizing polymers, in the dosage formcreates a microenvironment in the gastrointestinal tract in which thesalt of Compound 4 dissolves to provide the free acid and thestabilizing polymer, or combination of stabilizing polymers, thenfunctions to maintain the free acid in a supersaturated state insolution rather than precipitating out of solution. Because the amountof dissolved free acid increases and free acid precipitation is reduced,a larger amount of the administered dose is absorbed and thebioavailability of Compound 4 is increased.

As a result, the drug loading in a unit dose formulation comprising asalt of Compound 4 and a stabilizing polymer, or combination ofstabilizing polymers, can be reduced without a reduction in Compound 4bioavailability relative to a similar unit dose formulation having ahigher drug loading but otherwise lacking a sufficient amount of thestabilizing polymer, or combination of stabilizing polymers. Byfacilitating a reduction in the required drug loading of the unit dosageform, the stabilizing polymer, or combination of stabilizing polymers,effectively facilitates a corresponding reduction in the size of theunit dosage form where desirable.

Pharmaceutically acceptable stabilizing polymers, or combinations ofpharmaceutically acceptable stabilizing polymers, generally willinclude, for example, compressible stabilizing polymers, or compressiblecombinations of stabilizing polymers, and non-acidic stabilizingpolymers, or non-acidic combinations of stabilizing polymers. In oneaspect, the stabilizing polymer, or combination of pharmaceuticallyacceptable stabilizing polymers, comprises a compressible stabilizingpolymer, or compressible combination of stabilizing polymers. In anotheraspect, the stabilizing polymer, or combination of pharmaceuticallyacceptable stabilizing polymers, comprises a non-acidic polymer, ornon-acidic combination of stabilizing polymers.

Specific pharmaceutically acceptable stabilizing polymers, orcombinations of pharmaceutically acceptable stabilizing polymers,include stabilizing polymers, or combinations of stabilizing polymers,selected from the group consisting of copovidone, polyvinylpyrrolidone,hydroxypropyl methylcellulose, polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer (SOLUPLUS®), andcombinations thereof; wherein the hydroxypropyl methylcellulose has aviscosity less than 100 centipoise in a 2% solution (i.e., a 2% aqueoussolution) at a temperature of 20° C. In one aspect, the stabilizingpolymer, or combination of stabilizing polymers, is selected from thegroup consisting of copovidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, and combinations thereof; wherein the hydroxypropylmethylcellulose has a viscosity less than 100 centipoise in a 2%solution at a temperature of 20° C. In another aspect, the stabilizingpolymer, or combination of stabilizing polymers, is selected from thegroup consisting of homopolymers or copolymers of N-vinyl pyrrolidoneand cellulose esters. In another aspect, the stabilizing polymer, orcombination of stabilizing polymers, comprises copovidone. In anotheraspect, the stabilizing polymer, or combination of stabilizing polymers,comprises polyvinylpyrrolidone. In another aspect, the stabilizingpolymer, or combination of stabilizing polymers, comprises hydroxypropylmethylcellulose having a viscosity less than 100 centipoise in a 2%solution at a temperature of 20° C. In another aspect, the stabilizingpolymer, or combination of stabilizing polymers, comprises polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer(SOLUPLUS®). In another aspect, the dosage form comprises two or morestabilizing polymers selected from the group consisting of copovidone,polyvinylpyrrolidone, hydroxypropyl methylcellulose, and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer(SOLUPLUS®); wherein the hydroxypropyl methylcellulose has a viscosityless than 100 centipoise in a 2% solution at a temperature of 20° C.

F. Release Rate-Modifying Polymer

The amount of the release rate-modifying polymer, or combination ofrelease rate-modifying polymers, in the second composition generally isat least 5% by weight of the second composition. In one aspect, theamount of the release rate-modifying polymer, or combination of releaserate-modifying polymers, in the second composition is at least 10% byweight. In another aspect, the amount of the release rate-modifyingpolymer, or combination of release rate-modifying polymers, in thesecond composition is at least 15% by weight. In another aspect, theamount of the release rate-modifying polymer, or combination of releaserate-modifying polymers, in the second composition is at least 20% byweight. In another aspect, the amount of the release rate-modifyingpolymer, or combination of release rate-modifying polymers, in thesecond composition is 5% to 60% percent by weight. In another aspect,the amount of the release rate-modifying polymer, or combination ofrelease rate-modifying polymers, in the second composition is 10% to 50%percent by weight. In another aspect, the amount of the releaserate-modifying polymer, or combination of release rate-modifyingpolymers, in the second composition is 15% to 40% percent by weight. Inanother aspect, the amount of the release rate-modifying polymer, orcombination of release rate-modifying polymers, in the secondcomposition is 15% to 30% percent by weight.

In one embodiment, the weight ratio of the release rate-modifyingpolymer, or combination of release rate-modifying polymers, to Compound4 (free acid equivalent weight) in the second composition is from 4:1 to1:8. In one aspect, the weight ratio of the release rate-modifyingpolymer, or combination of release rate-modifying polymers, to Compound4 (free acid equivalent weight) in the second composition is 1:4 to 4:1.In another aspect, the weight ratio of the release rate-modifyingpolymer, or combination of release rate-modifying polymers, to Compound4 (free acid equivalent weight) in the second composition is the weightratio of the release rate-modifying polymer, or combination of releaserate-modifying polymers, to Compound 4 (free acid equivalent weight) inthe second composition is 1:3 to 2:1. In another aspect, the weightratio of the release rate-modifying polymer, or combination of releaserate-modifying polymers, to Compound 4 (free acid equivalent weight) inthe second composition is 1:2.5 to 1:1.

Pharmaceutically acceptable release rate-modifying polymers, orcombinations of pharmaceutically acceptable release rate-modifyingpolymers, generally will include, for example, compressible releaserate-modifying polymers, or compressible combinations of releaserate-modifying polymers, and non-acidic release rate-modifying polymers,or non-acidic combinations of release rate-modifying polymers. In oneaspect, the release rate-modifying polymer, or combination ofpharmaceutically acceptable release rate-modifying polymers, comprises acompressible release rate-modifying polymer, or compressible combinationof release rate-modifying polymers. In another aspect, the releaserate-modifying polymer, or combination of pharmaceutically acceptablerelease rate-modifying polymers, comprises a non-acidic polymer, ornon-acidic combination of release rate-modifying polymers.

Specific pharmaceutically acceptable release rate-modifying polymers, orcombinations of pharmaceutically acceptable release rate-modifyingpolymers, include release rate-modifying polymers, or combinations ofrelease rate-modifying polymers, selected from the group consisting ofpolyvinylpyrolidone, hydroxypropyl methylcellulose, ethylcellulosepolymers, copovidone, polyvinyl acetate, methacrylate/methacrylic freeacid copolymers, polyethylene glycols, polyethylene oxides, andpolaxamers. In one aspect, the release rate-modifying polymers, orcombinations of pharmaceutically acceptable release rate-modifyingpolymers, are selected from the group consisting of polyvinylpyrolidone(such as polyvinylpyrolidone (PVP) K17, PVP K25, PVP K30, and PVP K90);hydroxypropyl methylcellulose (such as hydroxypropyl methylcellulose(HPMC) E3, HPMC E5, HPMC E6, HPMC E15, HPMC E4M, HPMC E10M, HPMC K3,HPMC A4, HPMC A15, HPMC acetate succinate (AS) LF, HPMC AS MF, HPMC ASHF, HPMC AS LG, HPMC AS MG, HPMC AS HG, HPMC phthalate (P) 50, and HPMCP550; ethylcellulose polymers (such as Ethocel 4, Ethocel 7, Ethocel 10,Ethocel 14, and Ethocel 20); copovidone (vinylpyrrolidone-vinyl acetatecopolymer 60/40), polyvinyl acetate, polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer (SOLUPLUS®),methacrylate/methacrylic free acid copolymers (such as Eudragit L100-55,Eudragit L100, and Eudragit S100); polyethylene glycols (such aspolyethylene glycol (PEG) 400, PEG 600, PEG 1450, PEG 3350, PEG 4000,PEG 6000, and PEG 8000); and polaxamers (such as poloxamer 124,poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407). Inanother aspect, the release rate-modifying polymer, or combination ofrelease rate-modifying polymers, is selected from the group consistingof copovidone, polyvinylpyrrolidone, and hydroxypropyl methylcellulose.In another aspect, the release rate-modifying polymer, or combination ofrelease rate-modifying polymers, comprises hydroxypropylmethylcellulose. In another aspect, the release rate-modifying polymer,or combination of release rate-modifying polymers, compriseshydroxypropyl methylcellulose giving an apparent viscosity at 2% weightin water at 20° C. of 80 centipoise to 120,000 centipoise at 20° C. Inanother aspect, the release rate-modifying polymer, or combination ofrelease rate-modifying polymers, comprises a hydroxypropylmethylcellulose selected from the group consisting of K100, K4M, K15M,and K100M hydroxypropyl methylcelluloses.

In one embodiment of the dosage forms of the present disclosure, thestabilizing polymer comprises copovidone and the release rate-modifyingpolymer comprises hydroxypropyl methylcellulose.

G. Granulation

The Compound 4 starting material employed in the preparation of thedosage form can be granulated or ungranulated. It may be beneficial touse granulated Compound 4, for example, to improve bulk handlingproperties of the Compound 4 starting material during the preparation ofthe dosage form. In one embodiment, at least a portion of the Compound 4used in the preparation of the dosage form (e.g., as the Compound 4starting material for the first composition, the second composition, orboth) is provided in the form of granules comprising Compound 4, whereinthe granules are prepared by granulating Compound 4 with at least aportion of one or more of the excipients (see Section II.I. below)present in the dosage form.

In one embodiment, the dosage form is prepared by a process comprising:

-   -   granulating (i) a mixture comprising at least a portion of the        Compound 4 with at least a portion of the stabilizing polymer,        or combination of stabilizing polymers, to provide granules        comprising Compound 4; (ii) a mixture comprising at least a        portion of the Compound 4 with at least a portion of the release        rate-modifying polymer, or combination of release rate-modifying        polymers, to provide granules comprising Compound 4; or (iii) a        mixture comprising at least a portion of the Compound 4 with at        least a portion of the stabilizing polymer, or combination of        stabilizing polymers, and at least a portion of the release        rate-modifying polymer, or combination of stabilizing polymers,        to provide granules comprising Compound 4; and    -   preparing the second composition using the granules as a source        of at least a portion of the Compound 4 present in the second        composition.

As previously discussed, a portion of the total amount of Compound 4 inthe dosage form also may be present in the first composition. In suchdosage forms, at least a portion of the Compound 4 used in thepreparation of the first composition can be provided in the form ofgranules comprising Compound 4, wherein the granules are prepared bygranulating Compound 4 with at least a portion of the stabilizingpolymer, or combination of stabilizing polymers. In one embodiment, thedosage form is prepared by a process comprising:

-   -   granulating a mixture comprising at least a portion of the        Compound 4 with at least a portion of the stabilizing polymer,        or combination of stabilizing polymers, to provide granules        comprising Compound 4; and    -   preparing the first composition using the granules as a source        of at least a portion of the Compound 4 present in the first        composition.

In another embodiment, the dosage form is prepared by a processcomprising:

-   -   granulating a mixture comprising at least a portion of the        Compound 4 with at least a portion of the stabilizing polymer,        or combination of stabilizing polymers, to provide granules        comprising Compound 4;    -   preparing the first composition using the granules as a source        of at least a portion of the Compound 4 present in the first        composition; and    -   preparing the second composition using the granules as a source        of at least a portion of the Compound 4 present in the second        composition.

In another embodiment, the dosage form is prepared by a processcomprising:

-   -   granulating (i) a mixture comprising at least a portion of the        Compound 4 with at least a portion of the stabilizing polymer,        or combination of stabilizing polymers, to provide a first        population of granules comprising Compound 4;    -   granulating (i) a mixture comprising at least a portion of the        Compound 4 with at least a portion of the release rate-modifying        polymer, or combination of release rate-modifying polymers, to        provide a second population of granules comprising Compound 4;        or (ii) a mixture comprising at least a portion of the Compound        4 with at least a portion of the stabilizing polymer, or        combination of stabilizing polymers, and at least a portion of        the release rate-modifying polymer, or combination of        stabilizing polymers, to provide a second population of granules        comprising Compound 4;    -   preparing the first composition using the first population of        granules as a source of at least a portion of the Compound 4        present in the first composition; and    -   preparing the second composition using the second population of        granules as a source of at least a portion of the Compound 4        present in the second composition.

In another embodiment, at least a portion of the Compound 4 is drygranulated during the preparation of the dosage form with at least aportion of one or more of the excipients that are present in the finaldosage form.

In another embodiment, at least a portion of the Compound 4 is wetgranulated during the preparation of the dosage form with at least aportion of one or more of the excipients that are present in the finaldosage form. In one aspect, at least a portion of the Compound 4 is wet(high shear) granulated with at least a portion of one or more of theexcipients that are present in the final dosage form. In another aspect,a liquid comprising water is added to the granulation mixture during wetgranulation.

In another embodiment, at least a portion of the Compound 4 is fluid bedgranulated during the preparation of the dosage form with at least aportion of one or more of the excipients that are present in the finaldosage form. In one aspect, a liquid comprising water is added to thegranulation mixture during the fluid bed granulation. In another aspect,the granulation mixture is sprayed with a liquid comprising water duringthe fluid bed granulation.

In general, the moisture content of the granulation mixture during fluidbed granulation is controlled to provide an acceptable level of adhesionbetween the Compound 4 particles and the copovidone particles. As theweight ratio of Compound 4 to total polymer in the granulation mixtureincreases (i.e., as the relative amount of Compound 4 present in thegranulation mixture increases), the target moisture content selected forthe granulation mixture during granulation typically will increase. Inaddition, it may be beneficial to maintain the granulation mixture inthe fluid bed at the specified moisture content for an additional periodof time (i.e., a “hold period”) to further facilitate additional growth,tighter particle size distribution, and/or improved mechanicalproperties of the granules. In one aspect, the granulation mixturecomprises no more than 20 weight percent liquid during the granulation.In another aspect, the granulation mixture comprises no more than 14weight percent liquid during the granulation. In another aspect, thegranulation mixture comprises from 5 weight percent liquid to 20 weightpercent liquid when the addition of the liquid to the granulationmixture has been completed (i.e., prior to drying the granulationmixture). In another aspect, the granulation mixture comprises from 8weight percent liquid to 14 weight percent liquid when the addition ofthe liquid to the granulation mixture has been completed.

In each and every embodiment, example, preference and aspect describedherein, at least a portion of the Compound 4 can be, for example, fluidbed granulated with (a) at least a portion of the pharmaceuticallyacceptable stabilizing polymer, or combination of pharmaceuticallyacceptable stabilizing polymers, and/or (b) at least a portion of thepharmaceutically acceptable release rate-modifying polymer, orcombination of pharmaceutically acceptable stabilizing polymers, priorto blending with the other components of the formulation; and the weightratio of Compound 4 (free acid equivalent weight) to total polymer(i.e., the combined weight of stabilizing polymer and releaserate-modifying polymer) in the resulting granules is from 4:1 to 1:8.

In each and every embodiment, example, preference and aspect describedherein, the Compound 4 starting material used in the granulation can,for example, have a particle size distribution that satisfies one ormore of the following conditions: (a) a D₁₀ particle size distributionless than 20 μm, (b) a D₅₀ particle size distribution less than 50 μm,and/or (c) a D₉₀ particle size distribution less than 150 μm. In oneaspect, the Compound 4 starting material has a D₉₀ particle sizedistribution less than 100 μm. In another aspect, the Compound 4starting material has a particle size distribution that satisfies one ormore of the following conditions: (a) a D₁₀ particle size distributionfrom 1 μm to 20 μm, (b) a D₅₀ particle size distribution from 10 μm to50 μm, and/or (c) a D₉₀ particle size distribution from 40 μm to 100 μm.

In each and every embodiment, example, preference, and aspect describedherein, the granules comprising Compound 4 can, for example, have aparticle size distribution after granulation, sieving, and/or millingand prior to compression that satisfies one or more of the followingconditions: (a) a D₁₀ particle size distribution less than 100 μm, (b) aD₅₀ particle size distribution less than 300 μm, and/or (c) a D₉₀particle size distribution less than 600 μm. In one aspect, the granulescomprising Compound 4 have a particle size distribution aftergranulation, sieving, and/or milling and prior to compression thatsatisfies one or more of the following conditions: (a) a D₁₀ particlesize distribution from 1 μm to 100 μm, (b) a D₅₀ particle sizedistribution from 40 μm to 300 μm, and/or (c) a D₉₀ particle sizedistribution from 100 μm to 600 μm. In another aspect, the Compound 4granules have a particle size distribution after granulation, sieving,and/or milling and prior to compression that satisfies one or more ofthe following conditions: (a) a D₁₀ particle size distribution from 5 μmto 50 μm, (b) a D₅₀ particle size distribution from 80 μm to 130 μm,and/or (c) a D₉₀ particle size distribution from 180 μm to 250 μm.

Further discussion on granulation unit operations can be found, forexample, in Food and Drug Administration Guidance for Industry,SUPAC-IR/MR: Immediate Release and Modified Release Solid Oral DosageForms, Manufacturing Equipment Addendum (January 1999, CMC 9, Revision1).

H. Compounds 1, 2, and 3

The total drug loading in the first composition of the dosage formgenerally will be at least 5% by weight of the first composition. In oneaspect, the total amount of Compound 1 (free acid equivalent weight),Compound 2 (free base equivalent weight), and Compound 3 (free baseequivalent weight) in the first composition is at least 6% by weight ofthe first composition. In another aspect, the total amount is at least8% by weight. In another aspect, the total amount is at least 10% byweight. In another aspect, the total amount is at least 12% by weight.In another aspect, the total amount is 6% to 15% percent by weight. Inanother aspect, the total amount is 8% to 15% percent by weight. Inanother aspect, the total amount is 10% to 40% percent by weight. Inanother aspect, the total amount is 15% to 30% percent by weight. Inanother aspect, the total amount is 15% to 25% percent by weight. Inanother aspect, the total amount is 20% to 30% percent by weight. Inanother aspect, the first composition comprises Compound 1, Compound 2,and Compound 3 at a weight ratio (free acid or free base) of 3:2:24 to60:3:5 (Compound 1:Compound 2:Compound 3). In another aspect, the firstcomposition comprises Compound 1, Compound 2, and Compound 3 at a weightratio (free acid or free base) of 10:1:2 to 2:1:3 (Compound 1:Compound2:Compound 3). In another aspect, the weight ratio is 6:1:4 (Compound1:Compound 2:Compound 3).

In order to achieve the desired total drug loading, the firstcomposition typically will comprise Compound 1, Compound 2, and Compound3 in the form of an amorphous solid dispersion. In one embodiment,separate amorphous solid dispersions are prepared for each of Compound1, Compound 2, and Compound 3 (e.g., individual mono-extrudates) and theseparate amorphous solid dispersions are used to prepare the firstcomposition. In another embodiment, a single amorphous solid dispersioncomprising Compound 1, Compound 2, and Compound 3 (e.g., a co-extrudate)is prepared and used to prepare the first composition.

1. Individual Mono-Extrudates

In one embodiment of the present disclosure, each of the Compound 1,Compound 2, and Compound 3 components of the first composition isprepared as a separate amorphous solid dispersion comprising the activeingredient using hot melt extrusion technology and is milled prior toblending with the other two amorphous dispersions to form the firstcomposition. Accordingly, in one aspect of the dosage form, the firstcomposition comprises particles of a first amorphous solid dispersioncomprising Compound 1; particles of a second amorphous solid dispersioncomprising Compound 2; and particles of a third amorphous soliddispersion comprising Compound 3. In another aspect, the first amorphoussolid dispersion, second amorphous solid dispersion, and the thirdamorphous solid dispersion each independently comprise at least onepharmaceutically acceptable hydrophilic polymer and at least onepharmaceutically acceptable surfactant. In another aspect, eachhydrophilic polymer has a T_(g) value of at least 50° C. In anotheraspect, each hydrophilic polymer is a homopolymer or copolymer ofN-vinyl pyrrolidone. In another aspect, the hydrophilic polymer iscopovidone. In another aspect, each surfactant has aHydrophilic-Lipophilic Balance value of at least 10. In another aspect,one or more of the first amorphous solid dispersion, second amorphoussolid dispersion, and the third amorphous solid dispersion furthercomprises another surfactant having a Hydrophilic-Lipophilic Balancevalue of below 10. In another aspect, the first amorphous soliddispersion comprises propylene glycol monolaurate as the surfactant. Inanother aspect, the first amorphous solid dispersion further comprisesvitamin E tocopheryl polyethylene glycol succinate. In another aspect,the second amorphous solid dispersion comprises vitamin E tocopherylpolyethylene glycol succinate as the surfactant. In another aspect, thethird amorphous solid dispersion comprises sorbitan monolaurate as thesurfactant.

Additional information regarding the preparation of a Compound 1mono-extrudate, a Compound 2 mono-extrudate, and a Compound 3mono-extrudate can be found, for example, in published U.S. applicationUS2011/0312973 and published international application WO2011/156578,both of which are incorporated by reference.

2. Co-Extrudate

In another embodiment of the present disclosure, Compound 1, Compound 2,and Compound 3 are prepared as a single amorphous solid dispersioncomprising those three active ingredients using hot melt extrusiontechnology. The amorphous solid dispersion is milled and used to preparethe first composition.

Drug loads in conventional amorphous solid dispersions of poorly solublecompounds are generally no more than 15% by weight because higher drugloads can lead to a substantial reduction in drug release. Consequently,the Triple Tablet used in clinical trials was prepared from separatesolid dispersions of Compound 1, Compound 2, and Compound 3, with eachof the three solid dispersions having no more than 15% drug loading. Asa result of the low drug loading, the Triple Tablet was relatively largein size.

Moreover, hot melt extrusion, a method commonly used to prepareamorphous solid dispersions, often involves the use of high temperatureto assist the formation of a melt that is composed of all components ofthe final solid dispersion. Certain drug substances, such as Compound 3,can reach unacceptable degradation levels at temperatures of beyond 140°C., which considerably limits the use of the hot melt extrusion processto co-formulate Compound 3 with other drug substance(s) when the otherdrug substance(s) requires higher temperatures to form a suitable melt.

In contrast to conventional understanding, however, it has been foundthat Compound 1, Compound 2, and Compound 3 can be co-formulated in anamorphous solid dispersion having an increased total drug loadingwithout compromising drug release. This allows the preparation ofsmaller solid dosage forms (e.g., tablets) comprising all three drugsubstances. In addition, when Compound 1, Compound 2, and Compound 3were co-extruded in the hot melt extrusion process, Compound 3 becameless susceptible to degradation at high temperatures. Even at atemperature of 165° C., Compound 3 degradation was well within theacceptable levels.

In one embodiment of the present disclosure, the total weight ofCompound 1, Compound 2, and Compound 3 in the amorphous solid dispersionis at least 6% by weight relative to the total weight of the amorphoussolid dispersion. In one aspect, the total weight is at least 8% byweight relative to the total weight of the amorphous solid dispersion.In another aspect, the total weight is at least 10% by weight relativeto the total weight of the amorphous solid dispersion. In anotheraspect, the total weight is at least 12% by weight relative to the totalweight of the amorphous solid dispersion. In another aspect, the totalweight is at least 15% by weight relative to the total weight of theamorphous solid dispersion. In another aspect, the total weight is inexcess of 15% by weight relative to the total weight of the amorphoussolid dispersion. In another aspect, the total weight ranges from 10% to40% by weight relative to the total weight of the amorphous soliddispersion. In another aspect, the total weight ranges from 15% to 40%by weight relative to the total weight of the amorphous soliddispersion. In another aspect, the total weight ranges from 20% to 40%by weight relative to the total weight of the amorphous soliddispersion. In another aspect, the total weight ranges from 20% to 30%by weight relative to the total weight of the amorphous soliddispersion. In another aspect, the total weight ranges from 25% to 30%by weight relative to the total weight of the amorphous soliddispersion.

In another embodiment, Compound 1 in the amorphous solid dispersion canrange from 10% to 20% by weight relative to the total weight of theamorphous solid dispersion; Compound 2 in the amorphous solid dispersioncan range from 2% to 5% by weight relative to the total weight of theamorphous solid dispersion; and Compound 3 in the amorphous soliddispersion can range from 5% to 15% by weight relative to the totalweight of the amorphous solid dispersion. In one aspect, Compound 1 inthe amorphous solid dispersion can range from 15% to 20% by weightrelative to the total weight of the amorphous solid dispersion; Compound2 in the amorphous solid dispersion can range from 2% to 3% by weightrelative to the total weight of the amorphous solid dispersion; andCompound 3 in the amorphous solid dispersion can range from 10% to 15%by weight relative to the total weight of the amorphous soliddispersion. In another aspect, Compound 1 in the amorphous soliddispersion can be 15% by weight relative to the total weight of theamorphous solid dispersion; Compound 2 in the amorphous solid dispersioncan range from 2% to 3% by weight relative to the total weight of theamorphous solid dispersion; and Compound 3 in the amorphous soliddispersion can be 10% by weight relative to the total weight of theamorphous solid dispersion.

In another embodiment, the amount of Compound 1 in the amorphous soliddispersion can be, for example, 75 mg; the amount of Compound 2 in theamorphous solid dispersion can be, for example, 12.5 mg; and the amountof Compound 3 in the amorphous solid dispersion can be, for example, 50mg.

In another embodiment, the amorphous solid dispersion can comprise from50% to 75% by weight, relative to the total weight of the amorphoussolid dispersion, of the polymer, and from 2% to 15% by weight, relativeto the total weight of the amorphous solid dispersion, of thesurfactant. In one aspect, the amorphous solid dispersion can comprisefrom 50% to 70% by weight, relative to the total weight of the amorphoussolid dispersion, of the polymer, and from 5% to 15% by weight, relativeto the total weight of the amorphous solid dispersion, of thesurfactant. In another aspect, the amorphous solid dispersion cancomprise from 55% to 65% by weight, relative to the total weight of theamorphous solid dispersion, of the polymer, and from 5% to 10% byweight, relative to the total weight of the amorphous solid dispersion,of the surfactant. In another aspect, the amorphous solid dispersion cancomprise from 60% to 65% by weight, relative to the total weight of theamorphous solid dispersion, of the polymer, and from 5% to 10% byweight, relative to the total weight of the amorphous solid dispersion,of the surfactant.

In another embodiment, the amorphous solid dispersion can be prepared asa compressed core (e.g., a tablet core, layer, or the like), onto whichanother layer of other excipients or ingredients can be optionallyadded. For example, the amorphous solid dispersion can be milled, mixedwith other excipients or ingredients to form the first composition, andthe first composition compressed to form the core. In one aspect, thepolymer in the amorphous solid dispersion can range from 50% to 75% byweight relative to the total weight of the compressed core, and thesurfactant in the amorphous solid dispersion can range from 5 to 15% byweight relative to the total weight of the compressed core. In anotheraspect, the polymer in the amorphous solid dispersion can range from 50%to 70% by weight relative to the total weight of the compressed core,and the surfactant in the amorphous solid dispersion can range from 5 to15% by weight relative to the total weight of the compressed core. Inanother aspect, the polymer in the amorphous solid dispersion can rangefrom 55% to 65% by weight relative to the total weight of the compressedcore, and the surfactant in the amorphous solid dispersion can rangefrom 5 to 10% by weight relative to the total weight of the compressedcore. In another aspect, the polymer in the amorphous solid dispersioncan range from 60% to 65% by weight relative to the total weight of thecompressed core, and the surfactant in the amorphous solid dispersioncan range from 5 to 10% by weight relative to the total weight of thecompressed core.

In another embodiment, the total weight of Compound 1, Compound 2, andCompound 3 in the amorphous solid dispersion can range from 20% to 40%by weight relative to the total weight of the compressed core. In oneaspect, the total weight of Compound 1, Compound 2, and Compound 3 inthe amorphous solid dispersion can range from 20% to 30% by weightrelative to the total weight of the compressed core. In another aspect,the total weight of Compound 1, Compound 2, and Compound 3 in theamorphous solid dispersion can range from 25% to 30% by weight relativeto the total weight of the compressed core. In another aspect, Compound1 in the amorphous solid dispersion can range from 10% to 20% by weightrelative to the total weight of the compressed core; Compound 2 in theamorphous solid dispersion can range from 2% to 5% by weight relative tothe total weight of the compressed core; and Compound 3 in the amorphoussolid dispersion can range from 5% to 15% by weight relative to thetotal weight of the compressed core. In another aspect, Compound 1 inthe amorphous solid dispersion can range from 15% to 20% by weightrelative to the total weight of the compressed core; Compound 2 in theamorphous solid dispersion can range from 2% to 3% by weight relative tothe total weight of the compressed core; and Compound 3 in the amorphoussolid dispersion can range from 10% to 15% by weight relative to thetotal weight of the compressed core. In another aspect, Compound 1 inthe amorphous solid dispersion can be 15% by weight relative to thetotal weight of the compressed core; Compound 2 in the amorphous soliddispersion can range from 2% to 3% by weight relative to the totalweight of the compressed core; and Compound 3 in the amorphous soliddispersion can be 10% by weight relative to the total weight of thecompressed core.

In another embodiment, the hydrophilic polymer can have a T_(g) of atleast 50° C. In one aspect, the hydrophilic polymer has a T_(g) of atleast 80° C. In another aspect, the hydrophilic polymer has a T_(g) ofat least 100° C. In another aspect, the hydrophilic polymer can have aT_(g) of from 80° C. to 180° C. In another aspect, the hydrophilicpolymer can have a T_(g) of from 100° C. to 150° C.

Although the first composition can comprise a poorly water-soluble orwater-insoluble polymer (such as a cross-linked polymer), the firstcomposition generally will comprise a hydrophilic polymer that is awater-soluble polymer. In one aspect, the hydrophilic polymer has anapparent viscosity, when dissolved at 20° C. in an aqueous solution at2% (w/v), of 1 to 5000 mPa·s. In another aspect, the hydrophilic polymerhas an apparent viscosity, when dissolved at 20° C. in an aqueoussolution at 2% (w/v), of 1 to 700 mPa·s. In another aspect, thehydrophilic polymer has an apparent viscosity, when dissolved at 20° C.in an aqueous solution at 2% (w/v), of 5 to 100 mPa·s.

The hydrophilic polymer can be selected, for example, from the groupconsisting of homopolymer of N-vinyl lactam, copolymer of N-vinyllactam, cellulose ester, cellulose ether, polyalkylene oxide,polyacrylate, polymethacrylate, polyacrylamide, polyvinyl alcohol, vinylacetate polymer, oligosaccharide, polysaccharide, or combinationsthereof. Non-limiting examples of suitable hydrophilic polymers includehomopolymer of N-vinyl pyrrolidone, copolymer of N-vinyl pyrrolidone,copolymer of N-vinyl pyrrolidone and vinyl acetate, copolymer of N-vinylpyrrolidone and vinyl propionate, polyvinylpyrrolidone, methylcellulose,ethylcellulose, hydroxyalkylcelluloses, hydroxypropylcellulose,hydroxyalkylalkylcellulose, hydroxypropyl methylcellulose, cellulosephthalate, cellulose succinate, cellulose acetate phthalate,hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulosesuccinate, hydroxypropyl methylcellulose acetate succinate, polyethyleneoxide, polypropylene oxide, copolymer of ethylene oxide and propyleneoxide, methacrylic acid/ethyl acrylate copolymer, methacrylicacid/methyl methacrylate copolymer, butylmethacrylate/2-dimethylaminoethyl methacrylate copolymer,poly(hydroxyalkyl acrylate), poly(hydroxyalkyl methacrylate), copolymerof vinyl acetate and crotonic acid, partially hydrolyzed polyvinylacetate, carrageenan, galactomannan, xanthan gum, and combinationsthereof. In one aspect, the hydrophilic polymer is copovidone. Inanother aspect, the hydrophilic polymer is a homopolymer or copolymer ofN-vinyl pyrrolidone.

Although the first composition can comprise a surfactant having aHydrophobic-Lipophilic Balance (“HLB”) value less than 10, the firstcomposition generally will comprise a surfactant having an HLB value ofat least 10. In one embodiment, the first composition comprises a firstsurfactant having an HLB of at least 10 and a second surfactant havingan HLB value of less than 10, and both surfactants are co-formulated inthe amorphous solid dispersion.

The surfactant can be selected, for example, from the group consisistingof polyoxyethylene castor oil derivates, mono fatty acid ester ofpolyoxyethylene sorbitan, polyoxyethylene alkyl ether, polyoxyethylenealkylaryl ether, polyethylene glycol fatty acid ester, alkylene glycolfatty acid mono ester, sucrose fatty acid ester, sorbitan fatty acidmono ester, and combinations thereof. Non-limiting examples of suitablesurfactants include polyoxyethyleneglycerol triricinoleate or polyoxyl35 castor oil (Cremophor® EL; BASF Corp.) or polyoxyethyleneglyceroloxystearate such as polyethylenglycol 40 hydrogenated castor oil(Cremophor® RH 40, also known as polyoxyl 40 hydrogenated castor oil ormacrogolglycerol hydroxystearate) or polyethylenglycol 60 hydrogenatedcastor oil (Cremophor® RH 60), mono fatty acid ester of polyoxyethylenesorbitan, such as mono fatty acid ester of polyoxyethylene (20)sorbitan, e.g. polyoxyethylene (20) sorbitan monooleate (Tween® 80),polyoxyethylene (20) sorbitan monostearate (Tween® 60), polyoxyethylene(20) sorbitan monopalmitate (Tween® 40) or polyoxyethylene (20) sorbitanmonolaurate (Tween® 20), polyoxyethylene (3) lauryl ether,polyoxyethylene (5) cetyl ether, polyoxyethylene (2) stearyl ether,polyoxyethylene (5) stearyl ether, polyoxyethylene (2) nonylphenylether, polyoxyethylene (3) nonylphenyl ether, polyoxyethylene (4)nonylphenyl ether, polyoxyethylene (3) octylphenyl ether, PEG-200monolaurate, PEG-200 dilaurate, PEG-300 dilaurate, PEG-400 dilaurate,PEG-300 distearate, PEG-300 dioleate, propylene glycol monolaurate(e.g., Lauroglycol), sucrose monostearate, sucrose distearate, sucrosemonolaurate, sucrose dilaurate, sorbitan monolaurate, sorbitanmonooleate, sorbitan monopalnitate, sorbitan stearate, or combinationsthereof. In one aspect, the surfactant is D-alpha-tocopherylpolyethylene glycol 1000 succinate (vitamin E TPGS).

In one embodiment, the polymer is copovidone, and the surfactant isvitamin E TPGS. In another aspect, the polymer is copovidone, thesurfactant is vitamin E TPGS, and the amorphous solid dispersion furthercomprises propylene glycol monolaurate (e.g., Lauroglycol). Propyleneglycol monolaurate can range, for example, from 1% to 5% by weightrelative to the total weight of the amorphous solid dispersion.Propylene glycol monolaurate can also range, for example, from 1% to 3%by weight relative to the total weight of the amorphous soliddispersion.

In another embodiment, first composition comprises 75 mg of Compound 1,12.5 mg of Compound 2, and 50 mg of Compound 3, all of which areco-formulated with a pharmaceutically acceptable hydrophilic polymer anda pharmaceutically acceptable surfactant in amorphous solid dispersion,wherein the polymer in the amorphous solid dispersion ranges from 50% to70% by weight relative to the total weight of the amorphous soliddispersion, and the surfactant in the amorphous solid dispersion rangesfrom 5% to 15% by weight relative to the total weight of the amorphoussolid dispersion. In one aspect, the polymer is copovidone, and thesurfactant is vitamin E TPGS. In another aspect, the amorphous soliddispersion further comprises from 1% to 5% by weight of propylene glycolmonolaurate, relative to the total weight of the amorphous soliddispersion. In another aspect, the amorphous solid dispersion furthercomprises from 1% to 3% by weight of propylene glycol monolaurate.

In another embodiment, the first composition comprises 75 mg of Compound1, 12.5 mg of Compound 2, and 50 mg of Compound 3, all of which areco-formulated with a pharmaceutically acceptable hydrophilic polymer anda pharmaceutically acceptable surfactant in amorphous solid dispersion,wherein the polymer in the amorphous solid dispersion ranges from 55% to65% by weight relative to the total weight of the amorphous soliddispersion, and the surfactant in the amorphous solid dispersion rangesfrom 5% to 10% by weight relative to the total weight of the amorphoussolid dispersion. In one aspect, the polymer is copovidone, and thesurfactant is vitamin E TPGS. In another aspect, the amorphous soliddispersion further comprises from 1% to 5% by weight of propylene glycolmonolaurate, relative to the total weight of the amorphous soliddispersion. In another aspect, the amorphous solid dispersion furthercomprises from 1% to 3% by weight of propylene glycol monolaurate.

In another embodiment, the first composition comprises 75 mg of Compound1, 12.5 mg of Compound 2, and 50 mg of Compound 3, all of which areco-formulated with a pharmaceutically acceptable hydrophilic polymer anda pharmaceutically acceptable surfactant in amorphous solid dispersion,wherein the polymer in the amorphous solid dispersion ranges from 60% to65% by weight relative to the total weight of the amorphous soliddispersion, and the surfactant in the amorphous solid dispersion rangesfrom 5% to 10% by weight relative to the total weight of the amorphoussolid dispersion. In one aspect, the polymer is copovidone, and thesurfactant is vitamin E TPGS. In another aspect, the amorphous soliddispersion further comprises from 1% to 5% by weight of propylene glycolmonolaurate, relative to the total weight of the amorphous soliddispersion. In another aspect, the amorphous solid dispersion furthercomprises from 1% to 3% by weight of propylene glycol monolaurate.

In another embodiment, the first composition comprises a compressed corewhich includes 75 mg of Compound 1, 12.5 mg of Compound 2, and 50 mg ofCompound 3, all of which are co-formulated with a pharmaceuticallyacceptable hydrophilic polymer and a pharmaceutically acceptablesurfactant in amorphous solid dispersion, wherein the total weight ofthe compressed core is no more than 800 mg. In one aspect, the polymeris copovidone, and the surfactant is vitamin E TPGS, and the amorphoussolid dispersion further comprises propylene glycol monolaurate.

In another embodiment, the first composition comprises a compressed corewhich includes 75 mg of Compound 1, 12.5 mg of Compound 2, and 50 mg ofCompound 3, all of which are co-formulated with a pharmaceuticallyacceptable hydrophilic polymer and a pharmaceutically acceptablesurfactant in amorphous solid dispersion, wherein the total weight ofthe compressed core is no more than 700 mg. In one aspect, the polymeris copovidone, and the surfactant is vitamin E TPGS, and the amorphoussolid dispersion further comprises propylene glycol monolaurate.

In another embodiment, the first composition comprises a compressed corewhich includes 75 mg of Compound 1, 12.5 mg of Compound 2, and 50 mg ofCompound 3, all of which are co-formulated with a pharmaceuticallyacceptable hydrophilic polymer and a pharmaceutically acceptablesurfactant in amorphous solid dispersion, wherein the total weight ofthe compressed core is no more than 600 mg. In one aspect, the polymeris copovidone, and the surfactant is vitamin E TPGS, and the amorphoussolid dispersion further comprises propylene glycol monolaurate.

In another embodiment, the first composition comprises a compressed corewhich includes 75 mg of Compound 1, 12.5 mg of Compound 2, and 50 mg ofCompound 3, all of which are co-formulated with a pharmaceuticallyacceptable hydrophilic polymer and a pharmaceutically acceptablesurfactant in amorphous solid dispersion, wherein the total weight ofthe compressed core is no more than 500 mg. In one aspect, the polymeris copovidone, and the surfactant is vitamin E TPGS, and the amorphoussolid dispersion further comprises propylene glycol monolaurate.

In another embodiment, the first composition comprises a compressed corewhich includes 75 mg of Compound 1, 12.5 mg of Compound 2, and 50 mg ofCompound 3, all of which are co-formulated with a pharmaceuticallyacceptable hydrophilic polymer and a pharmaceutically acceptablesurfactant in amorphous solid dispersion, wherein the total weight ofthe compressed core ranges from 400 mg to 500 mg. In one aspect, thepolymer is copovidone, and the surfactant is vitamin E TPGS, and theamorphous solid dispersion further comprises propylene glycolmonolaurate.

In another embodiment, the first composition comprises a compressed corewhich includes 75 mg of Compound 1, 12.5 mg of Compound 2, and 50 mg ofCompound 3, all of which are co-formulated with a pharmaceuticallyacceptable hydrophilic polymer and a pharmaceutically acceptablesurfactant in amorphous solid dispersion, wherein the total weight ofthe compressed core ranges from 500 mg to 600 mg. In one aspect, thepolymer is copovidone, and the surfactant is vitamin E TPGS, and theamorphous solid dispersion further comprises propylene glycolmonolaurate.

In another embodiment, the first composition comprises a compressed corewhich includes 75 mg of Compound 1, 12.5 mg of Compound 2, and 50 mg ofCompound 3, all of which are co-formulated with a pharmaceuticallyacceptable hydrophilic polymer and a pharmaceutically acceptablesurfactant in amorphous solid dispersion, wherein the total weight ofthe compressed core ranges from 600 mg to 700 mg. In one aspect, thepolymer is copovidone, and the surfactant is vitamin E TPGS, and theamorphous solid dispersion further comprises propylene glycolmonolaurate

In another embodiment, the first composition comprises a compressed corewhich includes 75 mg of Compound 1, 12.5 mg of Compound 2, and 50 mg ofCompound 3, all of which are co-formulated with a pharmaceuticallyacceptable hydrophilic polymer and a pharmaceutically acceptablesurfactant in amorphous solid dispersion, wherein the total weight ofthe compressed core ranges from 450 mg to 500 mg. In one aspect, thepolymer is copovidone, and the surfactant is vitamin E TPGS, and theamorphous solid dispersion further comprises propylene glycolmonolaurate.

In another embodiment, the first composition comprises a compressed corewhich includes 75 mg of Compound 1, 12.5 mg of Compound 2, and 50 mg ofCompound 3, all of which are co-formulated with a pharmaceuticallyacceptable hydrophilic polymer and a pharmaceutically acceptablesurfactant in amorphous solid dispersion, wherein the total weight ofthe compressed core is 500 mg. In one aspect, the polymer is copovidone,and the surfactant is vitamin E TPGS, and the amorphous solid dispersionfurther comprises propylene glycol monolaurate.

In one embodiment, the amorphous solid dispersion is a solid solution,glass solution, or glass suspension. These types of amorphous soliddispersions are discussed, for example, in Chiou, W. L. and Riegelman,S. (1971), Pharmaceutical applications of solid dispersion systems. J.Pharm. Sci., 60: 1281-1302. In one aspect, the amorphous soliddispersion is a solid solution. In another embodiment, the amorphoussolid dispersion is a glassy solution.

In another embodiment, the amorphous solid dispersion comprises orconsists of a single-phase (as defined in thermodynamics) in whichCompound 1, Compound 2, and Compound 3 are molecularly dispersed in amatrix containing the pharmaceutically acceptable hydrophilic polymerand the pharmaceutically acceptable surfactant. Thermal analysis of theamorphous solid dispersion using differential scanning calorimetry (DSC)typically shows only one single T_(g), and the amorphous soliddispersion typically does not contain any detectable crystallinecompound as measured by X-ray powder diffraction spectroscopy.

I. Additional Excipients

The dosage form optionally may comprise other excipients such as, forexample, fillers, disintegrants, glidants, and lubricants. The term“excipient” is used in this disclosure to describe any ingredient otherthan Compound 1, Compound 2, Compound 3, or Compound 4. The choice ofadditional excipient(s) will depend to a large extent on factors suchas, for example, the effect of the excipient on solubility andstability. The drug loading requirements and resulting dosage form size,however, may effectively limit the amount of additional excipients thatmay be included in the dosage form.

Examples of pharmaceutically acceptable fillers include, withoutlimitation, microcrystalline cellulose, such as Avicel PH 101, AvicelPH102, Avicel PH 200, Avicel PH 105, Avicel DG, Ceolus KG 802, Ceolus KG1000, SMCC50 and Vivapur 200; lactose monohydrate, such as LactoseFastFlo; microcrystalline cellulose co-processed with other excipeints,such as microcrystalline cellulose co-processed with lactose monohydrate(MicroceLac 100) and microcrystalline cellulose co-processed withcolloidal silicon dioxide (SMCC50, Prosolv 50 and Prosolv HD 90);mixtures of isomaltulose derivatives such as galenlQ; natural orpre-gelatinized potato or corn starch; and other suitable fillers andcombinations thereof.

Examples of pharmaceutically acceptable disintegrants include, withoutlimitation, cross-linked polymers such as cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethylcellulose (includingcroscarmellose sodium).

Examples of pharmaceutically acceptable glidants include, withoutlimitation, colloidal silicon dioxide (such as highly dispersed silica(Aerosil®)) and any other suitable glidant such as animal or vegetablefats or waxes.

Examples of pharmaceutically acceptable lubricants include, withoutlimitation, polyethylene glycol (e.g., having a molecular weight of from1000 to 6000), magnesium stearate, calcium stearate, sodium stearylfumarate, and talc.

J. In Vitro and In Vivo Properties of Dosage Form

1. In Vitro Properties

In one aspect, the pharmaceutically acceptable release rate-modifyingpolymer, or combination of pharmaceutically acceptable releaserate-modifying polymers, modifies an in vitro release rate from thedosage form of at least one of the compounds within the dosage form tobe less than 75% to less than 35% of the in vitro release rate of thecompound from an otherwise identical dosage form lacking the releaserate-modifying polymer, or combination of release rate-modifyingpolymers.

In one aspect, the pharmaceutically acceptable release rate-modifyingpolymer, or combination of pharmaceutically acceptable releaserate-modifying polymers, modifies an in vitro release rate from thedosage form of at least one of the compounds within the dosage form tobe less than 75% to less than 35% of the in vitro release rate of thecompound from an otherwise identical dosage form lacking the releaserate-modifying polymer, or combination of release rate-modifyingpolymers as determined by a dissolution test conducted in 900 mL of adissolution medium comprising a 0.05 M sodium phosphate buffer pH 6.8with 15 mM cTAB as a surfactant using a standard USP dissolutionApparatus 2 (paddle) with sinker operating at 100 RPM at 37±0.5° C.

In one aspect, the pharmaceutically acceptable release rate-modifyingpolymer, or combination of pharmaceutically acceptable releaserate-modifying polymers, modifies an in vitro release rate from thedosage form of at least one of the compounds within the dosage form tobe an average in vitro release rate for the compound of 1.0 weightpercent/hour (based on the total weight of the compound in the dosageform) to 6.0 weight percent/hour over a sixteen-hour period. In oneaspect, the pharmaceutically acceptable release rate-modifying polymer,or combination of pharmaceutically acceptable release rate-modifyingpolymers, modifies an in vitro release rate from the dosage form of atleast one of the compounds within the dosage form to be an average invitro release rate for the compound of 1.0 weight percent/hour (based onthe total weight of the compound in the dosage form) to 6.0 weightpercent/hour over a sixteen-hour period as determined by a dissolutiontest conducted in 900 mL of a dissolution medium comprising a 0.05 Msodium phosphate buffer pH 6.8 with 15 mM cTAB as a surfactant using astandard USP dissolution Apparatus 2 (paddle) with sinker operating at100 RPM at 37±0.5° C.

In one aspect, the pharmaceutically acceptable release rate-modifyingpolymer, or combination of pharmaceutically acceptable releaserate-modifying polymers, modifies an in vitro release rate from thedosage form of at least one of the compounds within the dosage form tobe an average in vitro release rate for the compound of 5 mg/hour to 16mg/hour over a sixteen-hour period.

In one aspect, the pharmaceutically acceptable release rate-modifyingpolymer, or combination of pharmaceutically acceptable releaserate-modifying polymers, modifies an in vitro release rate from thedosage form of at least one of the compounds within the dosage form tobe an average in vitro release rate for the compound of 5 mg/hour to 16mg/hour over a sixteen-hour period as determined by a dissolution testconducted in 900 mL of a dissolution medium comprising a 0.05 M sodiumphosphate buffer pH 6.8 with 15 mM cTAB as a surfactant using a standardUSP dissolution Apparatus 2 (paddle) with sinker operating at 100 RPM at37±0.5° C.

a. Compound 4

In one aspect, the pharmaceutically acceptable release rate-modifyingpolymer, or combination of pharmaceutically acceptable releaserate-modifying polymers, modifies an in vitro release rate of Compound 4from the dosage form to be less than less than 75% to less than 35% ofthe in vitro release rate of Compound 4 from an otherwise identicaldosage form lacking the release rate-modifying polymer, or combinationof release rate-modifying polymers.

In one embodiment, the dosage forms of the present disclosure exhibit anin vitro release rate that is less than 75% of the in vitro release rateexhibited by an otherwise identical dosage form lacking the releaserate-modifying polymer, or combination of release rate-modifyingpolymers, wherein the in vitro release rate is determined using thedissolution test described below in Section II.J.1.c, and represents theaverage in vitro release rate (mg/hour) for Compound 4 over a four-hourperiod. In one aspect, the in vitro release rate is less than 65% of thein vitro release rate exhibited by an otherwise identical dosage formlacking the release rate-modifying polymer, or combination of releaserate-modifying polymers. In another aspect, the in vitro release rate isless than 55% of the in vitro release rate exhibited by an otherwiseidentical dosage form lacking the release rate-modifying polymer, orcombination of release rate-modifying polymers. In another aspect, thein vitro release rate is less than 45% of the in vitro release rateexhibited by an otherwise identical dosage form lacking the releaserate-modifying polymer, or combination of release rate-modifyingpolymers. In another aspect, the in vitro release rate is less than 35%of the in vitro release rate exhibited by an otherwise identical dosageform lacking the release rate-modifying polymer, or combination ofrelease rate-modifying polymers. In one aspect, the pharmaceuticallyacceptable release rate-modifying polymer, or combination ofpharmaceutically acceptable release rate-modifying polymers, modifies anin vitro release rate of Compound 4 from the dosage form to be anaverage in vitro release rate for of Compound 4 of 1.0 weightpercent/hour (based on the total weight of the compound in the dosageform) to 6.0 weight percent/hour over a sixteen-hour period.

In another embodiment, the dosage forms of the present disclosureexhibit an average in vitro release rate for Compound 4 over a 16 hourperiod of 1.0 weight percent/hour (based on the total weight of Compound4 in the dosage form) to 6.0 weight percent/hour as determined using thedissolution test described below in Section II.J.1.c. In one aspect, theaverage in vitro release rate over a 16 hour period is 1.5 weightpercent/hour to 5.5 weight percent/hour. In another aspect, the averagein vitro release rate over a 16 hour period is 2.0 weight percent/hourto 5.0 weight percent/hour. In another aspect, the average in vitrorelease rate over a 16 hour period is 2.0 weight percent/hour to 4.5weight percent/hour. In another aspect, the average in vitro releaserate over a 16 hour period is 2.0 weight percent/hour to 4.0 weightpercent/hour. In another aspect, the average in vitro release rate overa 16 hour period is 3.0 weight percent/hour to 3.5 weight percent/hour.

In one aspect, the pharmaceutically acceptable release rate-modifyingpolymer, or combination of pharmaceutically acceptable releaserate-modifying polymers, modifies an in vitro release rate of Compound 4from the dosage form to be an average in vitro release rate for thecompound over a 16 hour period of 1.0 weight percent/hour (based on thetotal weight of Compound 4 in the dosage form) to 6.0 weightpercent/hour as determined by a dissolution test conducted in 900 mL ofa dissolution medium comprising a 0.05 M sodium phosphate buffer pH 6.8with 15 mM cTAB as a surfactant using a standard USP dissolutionApparatus 2 (paddle) with sinker operating at 100 RPM at 37±0.5° C. Inone aspect, the pharmaceutically acceptable release rate-modifyingpolymer, or combination of pharmaceutically acceptable releaserate-modifying polymers, modifies an in vitro release rate of Compound 4from the dosage form to be an average in vitro release rate of 5 mg/hourto 16 mg/hour over a sixteen-hour period.

In one aspect, the pharmaceutically acceptable release rate-modifyingpolymer, or combination of pharmaceutically acceptable releaserate-modifying polymers, modifies an in vitro release rate of Compound 4from the dosage form to be an average in vitro release rate of 5 mg/hourto 16 mg/hour over a 16 hour period.

In another embodiment, the dosage forms of the present disclosureexhibit an average in vitro release rate for Compound 4 over a 16 hourperiod of 10 mg/hour to 16 mg/hour as determined using the dissolutiontest described below in Section II.J.1.c. In one aspect, the average invitro release rate over a 16 hour period is 10 mg/hour to 14 mg/hour. Inanother aspect, the average in vitro release rate over a 16 hour periodis 10 mg/hour to 12 mg/hour. In another aspect, the average in vitrorelease rate over a 16 hour period is 5 mg/hour to 10 mg/hour. Inanother aspect, the average in vitro release rate over a 16 hour periodis 6 mg/hour to 9 mg/hour. In another aspect, the average in vitrorelease rate over a 16 hour period is 7 mg/hour to 9 mg/hour.

In one aspect, the pharmaceutically acceptable release rate-modifyingpolymer, or combination of pharmaceutically acceptable releaserate-modifying polymers, modifies an in vitro release rate of Compound 4from the dosage form to be an average in vitro release rate for thecompound of 5 mg/hour to 16 mg/hour over a sixteen-hour period asdetermined by a dissolution test conducted in 900 mL of a dissolutionmedium comprising a 0.05 M sodium phosphate buffer pH 6.8 with 15 mMcTAB as a surfactant using a standard USP dissolution Apparatus 2(paddle) with sinker operating at 100 RPM at 37±0.5° C.

b. Compounds 1, 2, and 3

In one embodiment, the dosage forms of the present disclosure release atleast 40% by weight of each of Compounds 1, 2, and 3 within five hoursas determined using the dissolution test described below in SectionII.J.1.c. In one aspect, the dosage form releases at least 70% of eachof Compounds 1, 2, and 3 within ten hours. In one embodiment, the dosageforms of the present disclosure release at least 40% by weight of eachof Compounds 1, 2, and 3 within five hours, and at least 70% of each ofCompounds 1, 2, and 3 within ten hours.

In one embodiment, the dosage forms of the present disclosure release atleast 40% by weight of each of Compounds 1, 2, and 3 within five hours,and the dosage form releases at least 70% of each of Compounds 1, 2, and3 within ten hours as determined by a dissolution test conducted in 900mL of a dissolution medium comprising a 0.05 M sodium phosphate bufferpH 6.8 with 15 mM cTAB as a surfactant using a standard USP dissolutionApparatus 2 (paddle) with sinker operating at 100 RPM at 37±0.5° C.

c. Dissolution Test

The in vitro dissolution test used for evaluating the in vitro releaseproperties of the dosage form as described above in Sections II.J.1.aand II.J.1.b is conducted in 900 mL of a dissolution medium comprising a0.05 M sodium phosphate buffer pH 6.8 with 15 mM cTAB as a surfactantusing a standard USP dissolution Apparatus 2 (paddle) with sinkeroperating at 100 RPM at 37±0.5° C.

2. In Vivo Properties

While the dosage forms of the present disclosure generally will beadministered pursuant to a dosage regimen that comprises administeringone to four of the dosage forms once daily to the subject oradministering two or three of the dosage forms once daily to thesubject, each regimen is designed to provide in vivo results within atargeted therapeutic window.

a. Compound 4

In one embodiment, the present disclosure relates to dosage forms that,when administered once daily to a population of human subjects inaccordance with a dosing regimen that provides a daily therapeuticamount of Compounds 1, 2, 3, and 4 to the subject, satisfy one or moreof the following conditions:

-   -   (a) the average C_(max) value for Compound 4 in the population        of human subjects is from 400 ng/mL to 2,000 ng/mL;    -   (b) the average AUC_(∞) value for Compound 4 in the population        of human subjects is from 4,000 ng·hr/mL to 30,000 ng·hr/mL;    -   (c) the average T_(max) value for Compound 4 in the population        of human subjects is from 2.5 hours to 10 hours; and/or    -   (d) the average C₂₄ value for Compound 4 in the population of        human subjects is from 20 ng/mL to 400 ng/mL.        In one aspect, the daily dosing regimen comprises administering        two of the dosage forms once daily to the subject. In another        aspect, the daily dosing regimen comprises administering three        of the dosage forms once daily to the subject. In another        aspect, the dosage forms are administered under non-fasting        conditions. In another aspect, the dosage forms are administered        under fasting conditions. In another aspect, the daily dosing        regimen comprises administering the two or more dosage forms at        substantially the same time.

In another embodiment, the present disclosure relates to dosage formsthat, when administered once daily to a population of human subjects inaccordance with a dosing regimen that provides a daily therapeuticamount of Compounds 1, 2, 3, and 4 to the subject, satisfy one or moreof the following conditions:

-   -   (a) the average C_(max) value for Compound 4 in the population        of human subjects is from 750 ng/mL to 1,500 ng/mL;    -   (b) the average AUC_(∞) value for Compound 4 in the population        of human subjects is from 6,000 ng·hr/mL to 20,000 ng·hr/mL;    -   (c) the average T_(max) value for Compound 4 in the population        of human subjects is from 4 hours to 10 hours; and/or    -   (d) the average C₂₄ value for Compound 4 in the population of        human subjects is from 150 ng/mL to 400 ng/mL.

b. Compound 1

In one embodiment, the present disclosure relates to dosage forms that,when administered once daily to a population of human subjects inaccordance with a dosing regimen that provides a daily therapeuticamount of Compounds 1, 2, 3, and 4 to the subject, satisfy one or moreof the following conditions:

-   -   (a) the average C_(max) value for Compound 1 in the population        of human subjects is from 200 ng/mL to 4,000 ng/mL;    -   (b) the average AUC_(∞) value for Compound 1 in the population        of human subjects is from 2,000 ng·hr/mL to 25,000 ng·hr/mL;        and/or    -   (c) the average T_(max) value for Compound 1 in the population        of human subjects is from 3 hours to 8 hours.        In one aspect, the daily dosing regimen comprises administering        two of the dosage forms once daily to the subject. In another        aspect, the daily dosing regimen comprises administering three        of the dosage forms once daily to the subject. In another        aspect, the dosage forms are administered under non-fasting        conditions. In another aspect, the dosage forms are administered        under fasting conditions. In another aspect, the daily dosing        regimen comprises administering the two or more dosage forms at        substantially the same time.

In another embodiment, the present disclosure relates to dosage formsthat, when administered once daily to a population of human subjects inaccordance with a dosing regimen that provides a daily therapeuticamount of Compounds 1, 2, 3, and 4 to the subject, satisfy one or moreof the following conditions:

-   -   (a) the average C_(max) value for Compound 1 in the population        of human subjects is from 350 ng/mL to 2,200 ng/mL;    -   (b) the average AUC_(∞) value for Compound 1 in the population        of human subjects is from 2,500 ng·hr/mL to 15,000 ng·hr/mL;        and/or    -   (c) the average T_(max) value for Compound 1 in the population        of human subjects is from 4 hours to 7 hours.

c. Compound 2

In one embodiment, the present disclosure relates to dosage forms that,when administered once daily to a population of human subjects inaccordance with a dosing regimen that provides a daily therapeuticamount of Compounds 1, 2, 3, and 4 to the subject, satisfy one or moreof the following conditions:

-   -   (a) the average C_(max) value for Compound 2 in the population        of human subjects is from 50 ng/mL to 200 ng/mL;    -   (b) the average AUC_(∞) value for Compound 2 in the population        of human subjects is from 800 ng·hr/mL to 2,000 ng·hr/mL; and/or    -   (c) the average T_(max) value for Compound 2 in the population        of human subjects is from 3 hours to 7 hours.        In one aspect, the daily dosing regimen comprises administering        two of the dosage forms once daily to the subject. In another        aspect, the daily dosing regimen comprises administering three        of the dosage forms once daily to the subject. In another        aspect, the dosage forms are administered under non-fasting        conditions. In another aspect, the dosage forms are administered        under fasting conditions. In another aspect, the daily dosing        regimen comprises administering the two or more dosage forms at        substantially the same time.

In another embodiment, the present disclosure relates to dosage formsthat, when administered once daily to a population of human subjects inaccordance with a dosing regimen that provides a daily therapeuticamount of Compounds 1, 2, 3, and 4 to the subject, satisfy one or moreof the following conditions:

-   -   (a) the average C_(max) value for Compound 2 in the population        of human subjects is from 90 ng/mL to 180 ng/mL;    -   (b) the average AUC_(∞) value for Compound 2 in the population        of human subjects is from 1,000 ng·hr/mL to 2,000 ng·hr/mL;        and/or    -   (c) the average T_(max) value for Compound 2 in the population        of human subjects is from 4 hours to 6 hours.

d. Compound 3

In one embodiment, the present disclosure relates to dosage forms that,when administered once daily to a population of human subjects inaccordance with a dosing regimen that provides a daily therapeuticamount of Compounds 1, 2, 3, and 4 to the subject, satisfy one or moreof the following conditions:

-   -   (a) the average C_(max) value for Compound 3 in the population        of human subjects is from 500 ng/mL to 2,500 ng/mL;    -   (b) the average AUC_(∞) value for Compound 3 in the population        of human subjects is from 3,000 ng·hr/mL to 18,000 ng·hr/mL;        and/or    -   (c) the average T_(max) value for Compound 3 in the population        of human subjects is from 3 hours to 7 hours.

In one aspect, the daily dosing regimen comprises administering two ofthe dosage forms once daily to the subject. In another aspect, the dailydosing regimen comprises administering three of the dosage forms oncedaily to the subject. In another aspect, the dosage forms areadministered under non-fasting conditions. In another aspect, the dosageforms are administered under fasting conditions. In another aspect, thedaily dosing regimen comprises administering the two or more dosageforms at substantially the same time.

In another embodiment, the present disclosure relates to dosage formsthat, when administered once daily to a population of human subjects inaccordance with a dosing regimen that provides a daily therapeuticamount of Compounds 1, 2, 3, and 4 to the subject, satisfy one or moreof the following conditions:

-   -   (a) the average C_(m), value for Compound 3 in the population of        human subjects is from 700 ng/mL to 2.000 ng/mL;    -   (b) the average AUC_(∞) value for Compound 3 in the population        of human subjects is from 4,000 ng·hr/mL to 12,000 ng·hr/mL;        and/or    -   (c) the average T_(max) value for Compound 3 in the population        of human subjects is from 3.5 hours to 6 hours.

K. Dosage Form Size and Type

The dosage forms of the present disclosure generally will have a weightless than 1500 mg. In one aspect, oral dosage form has a weight lessthan 1450 mg. In another aspect, the dosage form has a weight less than1400 mg. In another aspect, the oral dosage form has a weight less than1350 mg.

In one embodiment, the dosage form is a tablet. In one aspect, thedosage form is a tablet having a weight from 500 mg to 1500 mg. Inanother aspect, the dosage form is a tablet having a weight from 900 mgto 1500 mg. In another aspect, the tablet is coated with a polymercoating. In another aspect, the tablet hardness is from 15 kP to 45 kP.In another aspect, the tablet hardness is from 25 kP to 35 kP.

In another embodiment, the dosage form is a tablet comprising at least afirst layer and a second layer. The first layer comprises the previouslydescribed first composition, and the second layer comprises thepreviously described second composition.

In another embodiment, the dosage form is a bilayer tablet comprising afirst layer comprising the previously described first composition and asecond layer comprising the previously described second composition.

In another embodiment, the dosage form is a trilayer tablet comprising afirst layer comprising the first composition, a second layer comprisingthe second composition, and a third layer comprising an immediaterelease composition comprising Compound 4.

In another embodiment, the dosage form is a tablet comprising a core andat least one exterior layer, wherein the core comprises the firstcomposition and the second composition; and the exterior layer comprisesCompound 4. In one aspect, the dosage form is a tablet comprising a coreand an exterior layer, wherein the core comprises the first compositionand the second composition; and the exterior layer comprises animmediate release composition comprising Compound 4.

In another embodiment, the dosage form is a tablet comprising at leastone outer layer comprising the active ingredients Compound 1, Compound2, Compound 3, and Compound 4, and a second inner core tablet comprisinga delayed release composition comprising Compound 4.

In another embodiment, the dosage form is a capsule comprising the firstcomposition and the second composition.

In another embodiment, the dosage form is a sachet comprising the firstcomposition and the second composition.

In another embodiment, the dosage form is a combination of mini-tablets.In one aspect, the dosage form comprising the combination ofmini-tablets is selected from the group consisting of a compresseddisintegrable tablet, an orally dispersible dosage form, a capsule, anda sachet. In another aspect, the dosage form comprising the combinationof mini-tablets is a compressed disintegrable tablet. In another aspect,the dosage form comprising the combination of mini-tablets is an orallydispersible dosage form. In another aspect, the dosage form comprisingthe combination of mini-tablets is a capsule. In another aspect, thedosage form comprising the combination of mini-tablets is a sachet. Inanother aspect, the combination of the mini-tablets comprises: (a) atleast one mini-tablet comprising the first composition; and (b) at leastone mini-tablet comprising the second composition. In another aspect,the combination of the mini-tablets comprises: (a) at least onemini-tablet comprising Compound 1; (b) at least one mini-tabletcomprising Compound 2; (c) at least one mini-tablet comprising Compound3; and (d) at least one mini-tablet comprising Compound 4.

In another embodiment, the dosage form comprises:

-   -   (a) a first population of particles comprising Compound 1;    -   (b) a second population of particles comprising Compound 2;    -   (c) a third population of particles comprising Compound 3; and    -   (d) a fourth population of particles comprising Compound 4;    -   wherein the fourth population comprises at least two        sub-populations of particles comprising Compound 4, and wherein        each sub-population exhibits a different in vitro release        profile for Compound 4 relative to the other sub-populations of        particles comprising Compound 4.

In one aspect of the above embodiment, the fourth population comprisesat least one sub-population of particles exhibiting an immediate releasein vitro release profile for Compound 4; at least one sub-population ofparticles exhibiting a delayed-release in vitro release profile forCompound 4; at least one sub-population of particles exhibiting anextended-release in vitro release profile for Compound 4. In anotheraspect, the particles comprising Compound 4 further comprise apharmaceutically acceptable stabilizing polymer, or combination ofpharmaceutically acceptable stabilizing polymers. In another aspect, atleast one of the sub-populations of particles comprising Compound 4further comprises a pharmaceutically acceptable release rate-modifyingpolymer, or combination of pharmaceutically acceptable releaserate-modifying polymers. In another aspect, the particles comprisingCompound 1 are in the form of an amorphous solid dispersion. In anotheraspect, the particles comprising Compound 2 are in the form of anamorphous solid dispersion. In another aspect, the particles comprisingCompound 3 are in the form of an amorphous solid dispersion. In anotheraspect, the weight ratio (free acid or free base) of Compound 1:Compound2:Compound 3 is from 10:1:2 to 2:1:3 (Compound 1:Compound 2:Compound 3).In another aspect, the weight ratio is 6:1:4 (Compound 1:Compound2:Compound 3).

In another embodiment, the dosage form is a sachet comprising the firstpopulation of particles, the second population of particles, the thirdpopulation of particles, and the fourth population of particles.

In another embodiment, the dosage form comprises:

-   -   (a) a first population of particles comprising Compound 1,        Compound 2, and Compound 3; and    -   (d) a second population of particles comprising Compound 4;    -   wherein the second population comprises at least two        sub-populations of particles comprising Compound 4, and wherein        each sub-population exhibits a different in vitro release        profile for Compound 4 relative to the other sub-populations of        particles comprising Compound 4.

In one aspect of the above embodiment, the second population comprisesat least one sub-population of particles exhibiting an immediate releasein vitro release profile for Compound 4; at least one sub-population ofparticles exhibiting a delayed-release in vitro release profile forCompound 4; at least one sub-population of particles exhibiting anextended-release in vitro release profile for Compound 4. In anotheraspect, the particles comprising Compound 4 further comprise apharmaceutically acceptable stabilizing polymer, or combination ofpharmaceutically acceptable stabilizing polymers. In another aspect, atleast one of the sub-populations of particles comprising Compound 4further comprises a pharmaceutically acceptable release rate-modifyingpolymer, or combination of pharmaceutically acceptable releaserate-modifying polymers. In another aspect, the particles comprisingCompound 1, Compound 2, and Compound 3 are in the form of an amorphoussolid dispersion. In another aspect, the weight ratio (free acid or freebase) of Compound 1:Compound 2:Compound 3 is from 3:2:24 to 60:3:5(Compound 1:Compound 2: Compound 3). In another aspect, the weight ratio(free acid or free base) of Compound 1:Compound 2:Compound 3 is from10:1:2 to 2:1:3 (Compound 1:Compound 2:Compound 3). In another aspect,the weight ratio is 6:1:4 (Compound 1:Compound 2:Compound 3).

In another embodiment, the dosage form is a sachet comprising the firstpopulation of particles and the second population of particles.

In another embodiment, the dosage form is an orally dispersible dosageform. The larger dosage form dimensions associated with a fixed dosecombination product due to the higher-drug loading can presentchallenges (such as swallowing difficulties) for certain patients,especially pediatric and geriatric patients. As a result, patientcompliance and use in pediatric patients may be limited. An orallydispersible dosage form (e.g., a dispersible dosage form that candisintegrate to fine dispersion within 30 seconds when in contact withwater) can overcome such problems associated with dosage form size.Since the dispersible dosage form yields a fine dispersion uponimmersion in water, the tablet dimensions should not impact patientcompliance. In general, the dispersible dosage form can be prepared inany suitable manner including freeze-drying and direct compressionmethods. Excipients may include a pharmaceutically acceptable dispersingagent (such as lactose, glucose, cyclodextrin, sucrose, xylitol,mannitol, and sorbitol), a pharmaceutically acceptable disintegrant(such as croscarmellose sodium, cross-linked PVP, sodium starchglycolate, maize starch, carboxymethyl cellulose calcium, carboxymethylcellulose sodium, and microcrystalline cellulose), and, optionally, apharmaceutically acceptable lubricant (such as magnesium stearate,calcium stearate, aluminum stearate, stearic acid, sodium stearylfumarate, talc, sodium benzoate, glyceryl mono fatty acid, glycerylmonostearate, glyceryl dibehenate, glyceryl palmito-stearic esters,polyethylene glycol, hydrogenated cotton seed oil, castor seed oil, andsucrose esters). The resulting blend can be incorporated into anysuitable dosage form which facilitates the release of the activeingredients. Examples of such dosage forms include but are not limitedto freeze-dried tablets, directly-compressed tablets, and lyophilizedpowders. The active ingredients can be provided, for example, in theform of individual mono-extrudates (Compounds 1, 2, and 3),co-extrudates (Compounds 1, 2, and 3), and mini-tablets.

L. Additional Representative Embodiments

In one embodiment, the solid dosage form comprises:

-   -   (a) Compound 1, wherein Compound 1 is:

or a pharmaceutically acceptable salt thereof;

-   -   (b) Compound 2, wherein Compound 2 is:

or a pharmaceutically acceptable salt thereof;

-   -   (c) Compound 3, wherein Compound 3 is ritonavir, or a        pharmaceutically acceptable salt thereof;    -   (d) Compound 4, wherein Compound 4 is:

or a pharmaceutically acceptable salt thereof; and

-   -   (e) a pharmaceutically acceptable stabilizing polymer, or        combination of pharmaceutically acceptable stabilizing polymers.

In one aspect of the solid dosage form: (a) Compound 1 is present in anamount of 40 mg to 180 mg (free acid equivalent weight); (b) Compound 2is present in an amount of 5 mg to 30 mg (free base equivalent weight);(c) Compound 3 is present in an amount of 25 mg to 120 mg (free baseequivalent weight); (d) Compound 4 is present in an amount of 75 mg to900 mg (free acid equivalent weight) of Compound 4; and (e) the dosageform comprises a pharmaceutically acceptable polymer, or combination ofpharmaceutically acceptable polymers in an amount of 350 mg to 2500 mg.In another aspect of the solid dosage form: (a) Compound 1 is present inan amount of 40 mg to 90 mg (free acid equivalent weight); (b) Compound2 is present in an amount of 5 mg to 15 mg (free base equivalentweight); (c) Compound 3 is present in an amount of 25 mg to 60 mg (freebase equivalent weight); (d) Compound 4 is present in an amount of 75 mgto 450 mg (free acid equivalent weight) of Compound 4; and (e) thedosage form comprises a pharmaceutically acceptable polymer, orcombination of pharmaceutically acceptable polymers in an amount of 400mg to 1500 mg. In another aspect of the solid dosage form: (a) Compound1 is present in an amount of 40 mg to 60 mg (free acid equivalentweight); (b) Compound 2 is present in an amount of 6.5 mg to 10.5 mg(free base equivalent weight); (c) Compound 3 is present in an amount of25 mg to 40 mg (free base equivalent weight); (d) Compound 4 is presentin an amount of 150 mg to 300 mg (free acid equivalent weight) ofCompound 4; and (e) the dosage form comprises a pharmaceuticallyacceptable polymer, or combination of pharmaceutically acceptablepolymers in an amount of 500 mg to 1000 mg. In another aspect of thesolid dosage form: (a) Compound 1 is present in an amount of 45 mg to 55mg (free acid equivalent weight); (b) Compound 2 is present in an amountof 7.5 mg to 9.5 mg (free base equivalent weight); (c) Compound 3 ispresent in an amount of 30 mg to 37 mg (free base equivalent weight);(d) Compound 4 is present in an amount of 150 mg to 300 mg (free acidequivalent weight) of Compound 4; and (e) the dosage form comprises apharmaceutically acceptable polymer, or combination of pharmaceuticallyacceptable polymers in an amount of 550 mg to 750 mg.

In one aspect of the embodiment, the solid dosage form comprises a firstcomposition comprising Compound 1, Compound 2, and Compound 3; and asecond composition comprising Compound 4. In another aspect, the soliddosage form comprises a first composition comprising Compound 1,Compound 2, Compound 3, and Compound 4; and a second compositioncomprising Compound 4. In one aspect, the dosage form is a bilayertablet comprising at least a first layer comprising the firstcomposition and at least a second layer comprising the secondcomposition. Unless otherwise specified, the terms “first layer” and“second layer” are used in a non-limiting manner and are intended toencompass bilayer tablets prepared in any tableting sequence (i.e., thefirst layer can prepared first followed by the second layer or thesecond layer can be prepared first followed by the first layer).

In one aspect, (a) the solid dosage form comprises a first compositioncomprising Compound 1, Compound 2, and Compound 3; and a secondcomposition comprising Compound 4; (b) Compound 1 is present in anamount of 40 mg to 180 mg (free acid equivalent weight); (c) Compound 2is present in an amount of 5 mg to 30 mg (free base equivalent weight);(d) Compound 3 is present in an amount of 25 mg to 120 mg (free baseequivalent weight); (e) Compound 4 is present in an amount of 75 mg to900 mg (free acid equivalent weight) of Compound 4; and (f) the secondcomposition comprises a pharmaceutically acceptable stabilizing polymer,or combination of pharmaceutically acceptable stabilizing polymers in anamount of 20 mg to 500 mg. In another aspect, (a) the solid dosage formcomprises a first composition comprising Compound 1, Compound 2, andCompound 3; and a second composition comprising Compound 4; (b) Compound1 is present in an amount of 40 mg to 90 mg (free acid equivalentweight); (c) Compound 2 is present in an amount of 5 mg to 15 mg (freebase equivalent weight); (d) Compound 3 is present in an amount of 25 mgto 60 mg (free base equivalent weight); (e) Compound 4 is present in anamount of 75 mg to 450 mg (free acid equivalent weight) of Compound 4;and (f) the second composition comprises a pharmaceutically acceptablestabilizing polymer, or combination of pharmaceutically acceptablestabilizing polymers in an amount of 25 mg to 400 mg. In another aspect,(a) the solid dosage form comprises a first composition comprisingCompound 1, Compound 2, and Compound 3; and a second compositioncomprising Compound 4; (b) Compound 1 is present in an amount of 40 mgto 60 mg (free acid equivalent weight); (c) Compound 2 is present in anamount of 6.5 mg to 10.5 mg (free base equivalent weight); (d) Compound3 is present in an amount of 25 mg to 40 mg (free base equivalentweight); (e) Compound 4 is present in an amount of 150 mg to 300 mg(free acid equivalent weight) of Compound 4; and (f) the secondcomposition comprises a pharmaceutically acceptable stabilizing polymer,or combination of pharmaceutically acceptable stabilizing polymers in anamount of 30 mg to 250 mg. In another aspect, (a) the solid dosage formcomprises a first composition comprising Compound 1, Compound 2, andCompound 3; and a second composition comprising Compound 4; (b) Compound1 is present in an amount of 45 mg to 55 mg (free acid equivalentweight); (c) Compound 2 is present in an amount of 7.5 mg to 9.5 mg(free base equivalent weight); (d) Compound 3 is present in an amount of30 mg to 37 mg (free base equivalent weight); (e) Compound 4 is presentin an amount of 150 mg to 300 mg (free acid equivalent weight) ofCompound 4; and (f) the second composition comprises a pharmaceuticallyacceptable stabilizing polymer, or combination of pharmaceuticallyacceptable stabilizing polymers in an amount of 50 mg to 150 mg. In eachof these aspects, the dosage form can be, for example, a bilayer tabletcomprising the first composition and the second composition.

In one aspect of the embodiment, the second composition furthercomprises the pharmaceutically acceptable stabilizing polymer, orcombination of pharmaceutically acceptable stabilizing polymers, in anamount of at least 5% by weight of the second composition. In anotheraspect, the stabilizing polymer, or combination of stabilizing polymersare selected from the group consisting of homopolymers or copolymers ofN-vinyl pyrrolidone and cellulose esters. In another aspect, thestabilizing polymer, or combination of stabilizing polymers, comprises astabilizing polymer selected from the group consisting of copovidone,polyvinylpyrrolidone, hydroxypropyl methylcellulose, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer(SOLUPLUS®), and combinations thereof; wherein the hydroxypropylmethylcellulose has a viscosity less than 100 centipoise in a 2%solution of at a temperature of 20° C. In another aspect, thestabilizing polymer, or combination of stabilizing polymers, comprisescopovidone.

In one aspect of the embodiment, the second composition furthercomprises a pharmaceutically acceptable release rate-modifying polymer,or combination of pharmaceutically acceptable release rate-modifyingpolymers, in an amount of at least 5% by weight of the secondcomposition. In another aspect, the release rate-modifying polymer, orcombination of release rate-modifying polymers, comprises a releaserate-modifying polymer selected from the group consisting of copovidone,polyvinylpyrrolidone, and hydroxypropyl methylcellulose. In anotheraspect, the stabilizing polymer, or combination of stabilizing polymers,comprises copovidone; and the release rate-modifying polymer, orcombination of release rate-modifying polymers comprises hydroxypropylmethylcellulose. In another aspect, the stabilizing polymer, orcombination of stabilizing polymers, and the release rate-modifyingpolymer, or combination of release rate-modifying polymers, are thesame.

In one aspect of the embodiment, the second composition furthercomprises the pharmaceutically acceptable stabilizing polymer, orcombination of pharmaceutically acceptable stabilizing polymers, in anamount of at least 5% by weight of the second composition; and furthercomprises a pharmaceutically acceptable release rate-modifying polymer,or combination of pharmaceutically acceptable release rate-modifyingpolymers, in an amount of at least 5% by weight of the secondcomposition. In another aspect, the stabilizing polymer, or combinationof stabilizing polymers are selected from the group consisting ofhomopolymers or copolymers of N-vinyl pyrrolidone and cellulose esters;and the release rate-modifying polymer, or combination of releaserate-modifying polymers, comprises a release rate-modifying polymerselected from the group consisting of copovidone, polyvinylpyrrolidone,and hydroxypropyl methylcellulose. In another aspect, the stabilizingpolymer, or combination of stabilizing polymers, comprises a stabilizingpolymer selected from the group consisting of copovidone,polyvinylpyrrolidone, hydroxypropyl methylcellulose, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer(SOLUPLUS®), and combinations thereof; wherein the hydroxypropylmethylcellulose has a viscosity less than 100 centipoise in a 2%solution of at a temperature of 20° C.; and the release rate-modifyingpolymer, or combination of release rate-modifying polymers, comprises arelease rate-modifying polymer selected from the group consisting ofcopovidone, polyvinylpyrrolidone, and hydroxypropyl methylcellulose. Inanother aspect, the stabilizing polymer, or combination of stabilizingpolymers, comprises copovidone; and the release rate-modifying polymer,or combination of release rate-modifying polymers compriseshydroxypropyl methylcellulose.

In one aspect of the embodiment, the first composition comprises anamorphous solid dispersion comprising one or more of Compound 1,Compound 2, and/or Compound 3. In another aspect, the amorphous soliddispersion further comprises at least one pharmaceutically acceptablehydrophilic polymer and at least one pharmaceutically acceptablesurfactant.

In one aspect of the embodiment, the D₉₀ particle size distribution forCompound 4 is less than 150 μm. In another aspect of the solid dosageform, the D₉₀ particle size distribution for Compound 4 is less than 100μm.

In one embodiment, the solid dosage form comprises:

-   -   (a) a first composition comprising:    -   (i) 40 mg to 90 mg (free acid equivalent weight) of Compound 1;    -   (ii) 5 mg to 15 mg (free base equivalent weight) of Compound 2;        and    -   (iii) 25 mg to 60 mg (free base equivalent weight) of Compound        3; and    -   (b) a second composition comprising:    -   (i) 75 mg to 450 mg (free acid equivalent weight) of Compound 4;    -   (ii) a pharmaceutically acceptable stabilizing polymer, or        combination of pharmaceutically acceptable stabilizing polymers,        in an amount from 10% by weight to 60% by weight of the second        composition; and    -   (iii) a pharmaceutically acceptable release rate-modifying        polymer, or combination of pharmaceutically acceptable release        rate-modifying polymers, in an amount from 5% by weight to 60%        by weight of the second composition.

In one embodiment, the solid dosage form comprises:

-   -   (a) a first composition comprising:    -   (i) 40 mg to 60 mg (free acid equivalent weight) of Compound 1;    -   (ii) 6.5 mg to 10.5 mg (free base equivalent weight) of Compound        2; and    -   (iii) 25 mg to 40 mg (free base equivalent weight) of Compound        3; and    -   (b) a second composition comprising:    -   (i) 150 mg to 300 mg (free acid equivalent weight) of Compound        4;    -   (ii) a pharmaceutically acceptable stabilizing polymer, or        combination of pharmaceutically acceptable stabilizing polymers,        in an amount from 15% by weight to 55% by weight of the second        composition; wherein the stabilizing polymer, or combination of        stabilizing polymers, comprises a stabilizing polymer selected        from the group consisting of copovidone, polyvinylpyrrolidone,        hydroxypropyl methylcellulose, polyvinyl caprolactam-polyvinyl        acetate-polyethylene glycol graft copolymer (SOLUPLUS®), and        combinations thereof; wherein the hydroxypropyl methylcellulose        has a viscosity less than 100 centipoise in a 2% solution of at        a temperature of 20° C.; and    -   (iii) a pharmaceutically acceptable release rate-modifying        polymer, or combination of pharmaceutically acceptable release        rate-modifying polymers, in an amount from 10% by weight to 50%        by weight of the second composition; wherein the release        rate-modifying polymer, or combination of release rate-modifying        polymers, comprises a release rate-modifying polymer selected        from the group consisting of polyvinylpyrolidone, hydroxypropyl        methylcellulose, ethylcellulose polymers, copovidone, polyvinyl        acetate, methacrylate/methacrylic free acid copolymers,        polyethylene glycols, and polaxamers.

In one embodiment, the solid dosage form comprises:

-   -   (a) a first composition comprising:    -   (i) 45 mg to 55 mg (free acid equivalent weight) of Compound 1;    -   (ii) 7.5 mg to 9.5 mg (free base equivalent weight) of Compound        2; and    -   (iii) 30 mg to 37 mg (free base equivalent weight) of Compound        3; and    -   (b) a second composition comprising:    -   (i) 150 mg to 300 mg (free acid equivalent weight) of Compound        4;    -   (ii) a pharmaceutically acceptable stabilizing polymer, or        combination of pharmaceutically acceptable stabilizing polymers,        in an amount from 15% by weight to 55% by weight of the second        composition; wherein the stabilizing polymer, or combination of        stabilizing polymers, comprises a stabilizing polymer selected        from the group consisting of copovidone, polyvinylpyrrolidone,        hydroxypropyl methylcellulose, polyvinyl caprolactam-polyvinyl        acetate-polyethylene glycol graft copolymer (SOLUPLUS®), and        combinations thereof; wherein the hydroxypropyl methylcellulose        has a viscosity less than 100 centipoise in a 2% solution of at        a temperature of 20° C.; and    -   (iii) a pharmaceutically acceptable release rate-modifying        polymer, or combination of pharmaceutically acceptable release        rate-modifying polymers, in an amount from 10% by weight to 50%        by weight of the second composition; wherein the release        rate-modifying polymer, or combination of release rate-modifying        polymers, comprises a release rate-modifying polymer selected        from the group consisting of copovidone, polyvinylpyrrolidone,        and hydroxypropyl methylcellulose.

In one embodiment, the solid dosage form comprises:

-   -   (a) a first composition comprising:    -   (i) 45 mg to 55 mg (free acid equivalent weight) of Compound 1;    -   (ii) 7.5 mg to 9.5 mg (free base equivalent weight) of Compound        2; and    -   (iii) 30 mg to 37 mg (free base equivalent weight) of Compound        3; and    -   (b) a second composition comprising:    -   (i) 150 mg to 300 mg (free acid equivalent weight) of Compound        4;    -   (ii) a pharmaceutically acceptable stabilizing polymer, or        combination of pharmaceutically acceptable stabilizing polymers,        in an amount from 20% by weight to 50% by weight of the second        composition; wherein the stabilizing polymer, or combination of        stabilizing polymers, comprises copovidone; and    -   (iii) a pharmaceutically acceptable release rate-modifying        polymer, or combination of pharmaceutically acceptable release        rate-modifying polymers, in an amount from 15% by weight to 40%        by weight of the second composition; wherein the release        rate-modifying polymer, or combination of release rate-modifying        polymers, comprises hydroxypropyl methylcellulose.

In one embodiment, the solid dosage form comprises:

-   -   (a) a first composition comprising:        -   (i) 50 mg (free acid equivalent weight) of Compound 1;        -   (ii) 8.3 mg (free base equivalent weight) of Compound 2; and        -   (iii) 33.3 mg (free base equivalent weight) of Compound 3;            and    -   (b) a second composition comprising:        -   (i) 150 mg to 300 mg (free acid equivalent weight) of            Compound 4; wherein the D90 particle size distribution for            the Compound 4 present in the dosage form is less than 100            μm;        -   (ii) a pharmaceutically acceptable stabilizing polymer, or            combination of pharmaceutically acceptable stabilizing            polymers, in an amount from 20% by weight to 50% by weight            of the second composition; wherein the stabilizing polymer,            or combination of stabilizing polymers, comprises            copovidone; and        -   (iii) a pharmaceutically acceptable release rate-modifying            polymer, or combination of pharmaceutically acceptable            release rate-modifying polymers, in an amount from 15% by            weight to 40% by weight of the second composition; wherein            the release rate-modifying polymer, or combination of            release rate-modifying polymers, comprises hydroxypropyl            methylcellulose.

In another embodiment, the present invention features a pharmaceuticalsolid dosage form comprising two compositions. The first compositioncomprises Compound 1, Compound 2 and Compound 3, each of which isformulated in amorphous solid dispersion, and the second compositioncomprises a pharmaceutically acceptable salt of Compound 4 in acrystalline form. The first composition comprises 5-10% Compound 1, 1-5%Compound 2, 2-8% Compound 3, 70-85% a pharmaceutically acceptablehydrophilic polymer or a combination of pharmaceutically acceptablehydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactantor a combination of pharmaceutically acceptable surfactants, wherein allpercentages are weight percentages relative to the total weight of thefirst composition. The second composition comprises 30-50% apharmaceutically acceptable salt of Compound 4, 20-40% apharmaceutically acceptable stabilizing polymer or a combination ofpharmaceutically acceptable stabilizing polymers, and 20-40% apharmaceutically acceptable release rate-modifying polymer or acombination of pharmaceutically acceptable release rate-modifyingpolymers, wherein all percentages are weight percentages relative to thetotal weight of the second composition.

In another embodiment, the present invention features a pharmaceuticalsolid dosage form comprising two compositions. The first compositioncomprises Compound 1, Compound 2 and Compound 3, each of which isformulated in amorphous solid dispersion, and the second compositioncomprises a pharmaceutically acceptable salt of Compound 4 in acrystalline form. The first composition comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptablehydrophilic polymer or a combination of pharmaceutically acceptablehydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactantor a combination of pharmaceutically acceptable surfactants, wherein allpercentages are weight percentages relative to the total weight of thefirst composition. The second composition comprises a pharmaceuticallyacceptable salt of Compound 4 in an amount equivalent to 200 mg Compound4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40% apharmaceutically acceptable stabilizing polymer or a combination ofpharmaceutically acceptable stabilizing polymers, and 20-40% apharmaceutically acceptable release rate-modifying polymer or acombination of pharmaceutically acceptable release rate-modifyingpolymers, wherein all percentages are weight percentages relative to thetotal weight of the second composition.

In yet another embodiment, the present invention features apharmaceutical solid dosage form comprising two compositions. The firstcomposition comprises Compound 1, Compound 2 and Compound 3, each ofwhich is formulated in amorphous solid dispersion, and the secondcomposition comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first composition comprises 50 mg Compound 1,8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceuticallyacceptable hydrophilic polymer or a combination of pharmaceuticallyacceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptablesurfactant or a combination of pharmaceutically acceptable surfactants,wherein all percentages are weight percentages relative to the totalweight of the first composition. The second composition comprises 216.2mg Compound 4 monosodium salt monohydrate, 20-40% a pharmaceuticallyacceptable stabilizing polymer or a combination of pharmaceuticallyacceptable stabilizing polymers, and 20-40% a pharmaceuticallyacceptable release rate-modifying polymer or a combination ofpharmaceutically acceptable release rate-modifying polymers, wherein allpercentages are weight percentages relative to the total weight of thesecond composition.

In yet another embodiment, the present invention features apharmaceutical solid dosage form comprising two compositions. The firstcomposition comprises Compound 1, Compound 2 and Compound 3, each ofwhich is formulated in amorphous solid dispersion, and the secondcomposition comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first composition comprises 5-10% Compound 1,1-5% Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, sorbitan monolaurate and lauroglycol,wherein all percentages are weight percentages relative to the totalweight of the first composition. The second composition comprises 30-50%a pharmaceutically acceptable salt of Compound 4, 20-40% copovidone, and20-40% hypromellose, wherein all percentages are weight percentagesrelative to the total weight of the second composition.

In yet another embodiment, the present invention features apharmaceutical solid dosage form comprising two compositions. The firstcomposition comprises Compound 1, Compound 2 and Compound 3, each ofwhich is formulated in amorphous solid dispersion, and the secondcomposition comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first composition comprises 50 mg Compound 1,8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, sorbitan monolaurate and lauroglycol,wherein all percentages are weight percentages relative to the totalweight of the first composition. The second composition comprises apharmaceutically acceptable salt of Compound 4 in an amount equivalentto 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium saltmonohydrate), 20-40% copovidone, and 20-40% hypromellose, wherein allpercentages are weight percentages relative to the total weight of thesecond composition.

In yet another embodiment, the present invention features apharmaceutical solid dosage form comprising two compositions. The firstcomposition comprises Compound 1, Compound 2 and Compound 3, each ofwhich is formulated in amorphous solid dispersion, and the secondcomposition comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first composition comprises 50 mg Compound 1,8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, sorbitan monolaurate and lauroglycol,wherein all percentages are weight percentages relative to the totalweight of the first composition. The second composition comprises 216.2mg Compound 4 monosodium salt monohydrate, 20-40% copovidone, and 20-40%hypromellose, wherein all percentages are weight percentages relative tothe total weight of the second composition.

In yet another embodiment, the present invention features apharmaceutical solid dosage form comprising two compositions. The firstcomposition comprises Compound 1, Compound 2 and Compound 3, each ofwhich is formulated in amorphous solid dispersion, and the secondcomposition comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first composition comprises 5-10% Compound 1,1-5% Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, sorbitan monolaurate and lauroglycol,wherein all percentages are weight percentages relative to the totalweight of the first composition. The second composition comprises 30-50%a pharmaceutically acceptable salt of Compound 4, 30% copovidone, and30% hypromellose, wherein all percentages are weight percentagesrelative to the total weight of the second composition.

In yet another embodiment, the present invention features apharmaceutical solid dosage form comprising two compositions. The firstcomposition comprises Compound 1, Compound 2 and Compound 3, each ofwhich is formulated in amorphous solid dispersion, and the secondcomposition comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first composition comprises 50 mg Compound 1,8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, sorbitan monolaurate and lauroglycol,wherein all percentages are weight percentages relative to the totalweight of the first composition. The second composition comprises apharmaceutically acceptable salt of Compound 4 in an amount equivalentto 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium saltmonohydrate), 30% copovidone, and 30% hypromellose, wherein allpercentages are weight percentages relative to the total weight of thesecond composition.

In yet another embodiment, the present invention features apharmaceutical solid dosage form comprising two compositions. The firstcomposition comprises Compound 1, Compound 2 and Compound 3, each ofwhich is formulated in amorphous solid dispersion, and the secondcomposition comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first composition comprises 50 mg Compound 1,8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, sorbitan monolaurate and lauroglycol,wherein all percentages are weight percentages relative to the totalweight of the first composition. The second composition comprises 216.2mg Compound 4 monosodium salt monohydrate, 30% copovidone, and 30%hypromellose, wherein all percentages are weight percentages relative tothe total weight of the second composition.

In another embodiment, the present invention features a pharmaceuticalsolid dosage form comprising two compositions. The first compositioncomprises Compound 1, Compound 2 and Compound 3, each of which isformulated in amorphous solid dispersion, and the second compositioncomprises a pharmaceutically acceptable salt of Compound 4 in acrystalline form. The first composition comprises 5-10% Compound 1, 1-5%Compound 2, 2-8% Compound 3, 70-85% a pharmaceutically acceptablehydrophilic polymer or a combination of pharmaceutically acceptablehydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactantor a combination of pharmaceutically acceptable surfactants, wherein allpercentages are weight percentages relative to the total weight of thefirst composition, and wherein Compound 1, Compound 2 and Compound 3 areformulated in the same amorphous solid dispersion which comprises (1)the hydrophilic polymer or the combination of hydrophilic polymers and(2) the surfactant or the combination of surfactants. The amorphoussolid dispersion can be milled and compressed into the firstcomposition. The second composition comprises 30-50% a pharmaceuticallyacceptable salt of Compound 4, 20-40% a pharmaceutically acceptablestabilizing polymer or a combination of pharmaceutically acceptablestabilizing polymers, and 20-40% a pharmaceutically acceptable releaserate-modifying polymer or a combination of pharmaceutically acceptablerelease rate-modifying polymers, wherein all percentages are weightpercentages relative to the total weight of the second composition.

In another embodiment, the present invention features a pharmaceuticalsolid dosage form comprising two compositions. The first compositioncomprises Compound 1, Compound 2 and Compound 3, each of which isformulated in amorphous solid dispersion, and the second compositioncomprises a pharmaceutically acceptable salt of Compound 4 in acrystalline form. The first composition comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptablehydrophilic polymer or a combination of pharmaceutically acceptablehydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactantor a combination of pharmaceutically acceptable surfactants, wherein allpercentages are weight percentages relative to the total weight of thefirst composition, and wherein Compound 1, Compound 2 and Compound 3 areformulated in the same amorphous solid dispersion which comprises (1)the hydrophilic polymer or the combination of hydrophilic polymers and(2) the surfactant or the combination of surfactants. The amorphoussolid dispersion can be milled and compressed into the firstcomposition. The second composition comprises a pharmaceuticallyacceptable salt of Compound 4 in an amount equivalent to 200 mg Compound4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40% apharmaceutically acceptable stabilizing polymer or a combination ofpharmaceutically acceptable stabilizing polymers, and 20-40% apharmaceutically acceptable release rate-modifying polymer or acombination of pharmaceutically acceptable release rate-modifyingpolymers, wherein all percentages are weight percentages relative to thetotal weight of the second composition.

In yet another embodiment, the present invention features apharmaceutical solid dosage form comprising two compositions. The firstcomposition comprises Compound 1, Compound 2 and Compound 3, each ofwhich is formulated in amorphous solid dispersion, and the secondcomposition comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first composition comprises 50 mg Compound 1,8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceuticallyacceptable hydrophilic polymer or a combination of pharmaceuticallyacceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptablesurfactant or a combination of pharmaceutically acceptable surfactants,wherein all percentages are weight percentages relative to the totalweight of the first composition, and wherein Compound 1, Compound 2 andCompound 3 are formulated in the same amorphous solid dispersion whichcomprises (1) the hydrophilic polymer or the combination of hydrophilicpolymers and (2) the surfactant or the combination of surfactants. Theamorphous solid dispersion can be milled and compressed into the firstcomposition. The second composition comprises 216.2 mg Compound 4monosodium salt monohydrate, 20-40% a pharmaceutically acceptablestabilizing polymer or a combination of pharmaceutically acceptablestabilizing polymers, and 20-40% a pharmaceutically acceptable releaserate-modifying polymer or a combination of pharmaceutically acceptablerelease rate-modifying polymers, wherein all percentages are weightpercentages relative to the total weight of the second composition.

In yet another embodiment, the present invention features apharmaceutical solid dosage form comprising two compositions. The firstcomposition comprises Compound 1, Compound 2 and Compound 3, each ofwhich is formulated in amorphous solid dispersion, and the secondcomposition comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first composition comprises 5-10% Compound 1,1-5% Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, sorbitan monolaurate and lauroglycol,wherein all percentages are weight percentages relative to the totalweight of the first composition, and wherein Compound 1, Compound 2 andCompound 3 are formulated in the same amorphous solid dispersion whichcomprises copovidone, vitamin E TPGS, lauroglycol and sorbitanmonolaurate. The amorphous solid dispersion can be milled and compressedinto the first composition. The second composition comprises 30-50% apharmaceutically acceptable salt of Compound 4, 20-40% copovidone, and20-40% hypromellose, wherein all percentages are weight percentagesrelative to the total weight of the second composition.

In yet another embodiment, the present invention features apharmaceutical solid dosage form comprising two compositions. The firstcomposition comprises Compound 1, Compound 2 and Compound 3, each ofwhich is formulated in amorphous solid dispersion, and the secondcomposition comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first composition comprises 50 mg Compound 1,8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first composition, and wherein Compound 1, Compound 2 andCompound 3 are formulated in the same amorphous solid dispersion whichcomprises copovidone, vitamin E TPGS, lauroglycol and sorbitanmonolaurate. The amorphous solid dispersion can be milled and compressedinto the first composition. The second composition comprises apharmaceutically acceptable salt of Compound 4 in an amount equivalentto 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium saltmonohydrate), 20-40% copovidone, and 20-40% hypromellose, wherein allpercentages are weight percentages relative to the total weight of thesecond composition.

In yet another embodiment, the present invention features apharmaceutical solid dosage form comprising two compositions. The firstcomposition comprises Compound 1, Compound 2 and Compound 3, each ofwhich is formulated in amorphous solid dispersion, and the secondcomposition comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first composition comprises 50 mg Compound 1,8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first composition, and wherein Compound 1, Compound 2 andCompound 3 are formulated in the same amorphous solid dispersion whichcomprises copovidone, vitamin E TPGS, lauroglycol and sorbitanmonolaurate. The amorphous solid dispersion can be milled and compressedinto the first composition. The second composition comprises 216.2 mgCompound 4 monosodium salt monohydrate, 20-40% copovidone, and 20-40%hypromellose, wherein all percentages are weight percentages relative tothe total weight of the second composition.

In yet another embodiment, the present invention features apharmaceutical solid dosage form comprising two compositions. The firstcomposition comprises Compound 1, Compound 2 and Compound 3, each ofwhich is formulated in amorphous solid dispersion, and the secondcomposition comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first composition comprises 5-10% Compound 1,1-5% Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first composition, and wherein Compound 1, Compound 2 andCompound 3 are formulated in the same amorphous solid dispersion whichcomprises copovidone, vitamin E TPGS, lauroglycol and sorbitanmonolaurate. The amorphous solid dispersion can be milled and compressedinto the first composition. The second composition comprises 30-50% apharmaceutically acceptable salt of Compound 4, 30% copovidone, and 30%hypromellose, wherein all percentages are weight percentages relative tothe total weight of the second composition.

In yet another embodiment, the present invention features apharmaceutical solid dosage form comprising two compositions. The firstcomposition comprises Compound 1, Compound 2 and Compound 3, each ofwhich is formulated in amorphous solid dispersion, and the secondcomposition comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first composition comprises 50 mg Compound 1,8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first composition, and wherein Compound 1, Compound 2 andCompound 3 are formulated in the same amorphous solid dispersion whichcomprises copovidone, vitamin E TPGS, lauroglycol and sorbitanmonolaurate. The amorphous solid dispersion can be milled and compressedinto the first composition. The second composition comprises apharmaceutically acceptable salt of Compound 4 in an amount equivalentto 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium saltmonohydrate), 30% copovidone, and 30% hypromellose, wherein allpercentages are weight percentages relative to the total weight of thesecond composition.

In yet another embodiment, the present invention features apharmaceutical solid dosage form comprising two compositions. The firstcomposition comprises Compound 1, Compound 2 and Compound 3, each ofwhich is formulated in amorphous solid dispersion, and the secondcomposition comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first composition comprises 50 mg Compound 1,8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first composition, and wherein Compound 1, Compound 2 andCompound 3 are formulated in the same amorphous solid dispersion whichcomprises copovidone, vitamin E TPGS, lauroglycol and sorbitanmonolaurate. The amorphous solid dispersion can be milled and compressedinto the first composition. The second composition comprises 216.2 mgCompound 4 monosodium salt monohydrate, 30% copovidone, and 30%hypromellose, wherein all percentages are weight percentages relative tothe total weight of the second composition.

In another embodiment, the present invention features a pharmaceuticalsolid dosage form comprising two compositions. The first compositioncomprises Compound 1, Compound 2 and Compound 3, each of which isformulated in amorphous solid dispersion, and the second compositioncomprises a pharmaceutically acceptable salt of Compound 4 in acrystalline form. The first composition comprises 5-10% Compound 1, 1-5%Compound 2, 2-8% Compound 3, 70-85% a pharmaceutically acceptablehydrophilic polymer or a combination of pharmaceutically acceptablehydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactantor a combination of pharmaceutically acceptable surfactants, wherein allpercentages are weight percentages relative to the total weight of thefirst composition, and wherein Compound 1, Compound 2 and Compound 3 areeach formulated in separate amorphous solid dispersions, and each soliddispersion comprises (1) the hydrophilic polymer or the combination ofhydrophilic polymers and (2) the surfactant or one of the combination ofsurfactants. These amorphous solid dispersions can be milled and thencompressed into the first composition. The second composition comprises30-50% a pharmaceutically acceptable salt of Compound 4, 20-40% apharmaceutically acceptable stabilizing polymer or a combination ofpharmaceutically acceptable stabilizing polymers, and 20-40% apharmaceutically acceptable release rate-modifying polymer or acombination of pharmaceutically acceptable release rate-modifyingpolymers, wherein all percentages are weight percentages relative to thetotal weight of the second composition.

In another embodiment, the present invention features a pharmaceuticalsolid dosage form comprising two compositions. The first compositioncomprises Compound 1, Compound 2 and Compound 3, each of which isformulated in amorphous solid dispersion, and the second compositioncomprises a pharmaceutically acceptable salt of Compound 4 in acrystalline form. The first composition comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptablehydrophilic polymer or a combination of pharmaceutically acceptablehydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactantor a combination of pharmaceutically acceptable surfactants, wherein allpercentages are weight percentages relative to the total weight of thefirst composition, and wherein Compound 1, Compound 2 and Compound 3 areeach formulated in separate amorphous solid dispersions, and each soliddispersion comprises (1) the hydrophilic polymer or one of thecombination of hydrophilic polymers and (2) the surfactant or one of thecombination of surfactants. These amorphous solid dispersions can bemilled and then compressed into the first composition. The secondcomposition comprises a pharmaceutically acceptable salt of Compound 4in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4monosodium salt monohydrate), 20-40% a pharmaceutically acceptablestabilizing polymer or a combination of pharmaceutically acceptablestabilizing polymers, and 20-40% a pharmaceutically acceptable releaserate-modifying polymer or a combination of pharmaceutically acceptablerelease rate-modifying polymers, wherein all percentages are weightpercentages relative to the total weight of the second composition.

In yet another embodiment, the present invention features apharmaceutical solid dosage form comprising two compositions. The firstcomposition comprises Compound 1, Compound 2 and Compound 3, each ofwhich is formulated in amorphous solid dispersion, and the secondcomposition comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first composition comprises 50 mg Compound 1,8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceuticallyacceptable hydrophilic polymer or a combination of pharmaceuticallyacceptable hydrophilic polymers, and 5-10% a pharmaceutically acceptablesurfactant or a combination of pharmaceutically acceptable surfactants,wherein all percentages are weight percentages relative to the totalweight of the first composition, and wherein Compound 1, Compound 2 andCompound 3 are each formulated in separate amorphous solid dispersions,and each solid dispersion comprises (1) the hydrophilic polymer or oneof the combination of hydrophilic polymers and (2) the surfactant or oneof the combination of surfactants. These amorphous solid dispersions canbe milled and then compressed into the first composition. The secondcomposition comprises 216.2 mg Compound 4 monosodium salt monohydrate,20-40% a pharmaceutically acceptable stabilizing polymer or acombination of pharmaceutically acceptable stabilizing polymers, and20-40% a pharmaceutically acceptable release rate-modifying polymer or acombination of pharmaceutically acceptable release rate-modifyingpolymers, wherein all percentages are weight percentages relative to thetotal weight of the second composition.

In yet another embodiment, the present invention features apharmaceutical solid dosage form comprising two compositions. The firstcomposition comprises Compound 1, Compound 2 and Compound 3, each ofwhich is formulated in amorphous solid dispersion, and the secondcomposition comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first composition comprises 5-10% Compound 1,1-5% Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, sorbitan monolaurate and lauroglycol,wherein all percentages are weight percentages relative to the totalweight of the first composition, and wherein Compound 1, Compound 2 andCompound 3 are each formulated in separate amorphous solid dispersions.The solid dispersion comprising Compound 1 can comprise copovidone,vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound2 can comprise copovidone and vitamin E TPGS; and the solid dispersioncomprising Compound 3 can comprise copovidone and sorbitan monolaurate.These amorphous solid dispersions can be milled and then compressed intothe first composition. The second composition comprises 30-50% apharmaceutically acceptable salt of Compound 4, 20-40% copovidone, and20-40% hypromellose, wherein all percentages are weight percentagesrelative to the total weight of the second composition.

In yet another embodiment, the present invention features apharmaceutical solid dosage form comprising two compositions. The firstcomposition comprises Compound 1, Compound 2 and Compound 3, each ofwhich is formulated in amorphous solid dispersion, and the secondcomposition comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first composition comprises 50 mg Compound 1,8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first composition, and wherein Compound 1, Compound 2 andCompound 3 are each formulated in separate amorphous solid dispersions.The solid dispersion comprising Compound 1 can comprise copovidone,vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound2 can comprise copovidone and vitamin E TPGS; and the solid dispersioncomprising Compound 3 can comprise copovidone and sorbitan monolaurate.These amorphous solid dispersions can be milled and then compressed intothe first composition. The second composition comprises apharmaceutically acceptable salt of Compound 4 in an amount equivalentto 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium saltmonohydrate), 20-40% copovidone, and 20-40% hypromellose, wherein allpercentages are weight percentages relative to the total weight of thesecond composition.

In yet another embodiment, the present invention features apharmaceutical solid dosage form comprising two compositions. The firstcomposition comprises Compound 1, Compound 2 and Compound 3, each ofwhich is formulated in amorphous solid dispersion, and the secondcomposition comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first composition comprises 50 mg Compound 1,8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first composition, and wherein Compound 1, Compound 2 andCompound 3 are each formulated in separate amorphous solid dispersions.The solid dispersion comprising Compound 1 can comprise copovidone,vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound2 can comprise copovidone and vitamin E TPGS; and the solid dispersioncomprising Compound 3 can comprise copovidone and sorbitan monolaurate.These amorphous solid dispersions can be milled and then compressed intothe first composition. The second composition comprises 216.2 mgCompound 4 monosodium salt monohydrate, 20-40% copovidone, and 20-40%hypromellose, wherein all percentages are weight percentages relative tothe total weight of the second composition.

In yet another embodiment, the present invention features apharmaceutical solid dosage form comprising two compositions. The firstcomposition comprises Compound 1, Compound 2 and Compound 3, each ofwhich is formulated in amorphous solid dispersion, and the secondcomposition comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first composition comprises 5-10% Compound 1,1-5% Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first composition, and wherein Compound 1, Compound 2 andCompound 3 are each formulated in separate amorphous solid dispersions.The solid dispersion comprising Compound 1 can comprise copovidone,vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound2 can comprise copovidone and vitamin E TPGS; and the solid dispersioncomprising Compound 3 can comprise copovidone and sorbitan monolaurate.These amorphous solid dispersions can be milled and then compressed intothe first composition. The second composition comprises 30-50% apharmaceutically acceptable salt of Compound 4, 30% copovidone, and 30%hypromellose, wherein all percentages are weight percentages relative tothe total weight of the second composition.

In yet another embodiment, the present invention features apharmaceutical solid dosage form comprising two compositions. The firstcomposition comprises Compound 1, Compound 2 and Compound 3, each ofwhich is formulated in amorphous solid dispersion, and the secondcomposition comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first composition comprises 50 mg Compound 1,8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first composition, and wherein Compound 1, Compound 2 andCompound 3 are each formulated in separate amorphous solid dispersions.The solid dispersion comprising Compound 1 can comprise copovidone,vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound2 can comprise copovidone and vitamin E TPGS; and the solid dispersioncomprising Compound 3 can comprise copovidone and sorbitan monolaurate.These amorphous solid dispersions can be milled and then compressed intothe first composition. The second composition comprises apharmaceutically acceptable salt of Compound 4 in an amount equivalentto 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium saltmonohydrate), 30% copovidone, and 30% hypromellose, wherein allpercentages are weight percentages relative to the total weight of thesecond composition.

In yet another embodiment, the present invention features apharmaceutical solid dosage form comprising two compositions. The firstcomposition comprises Compound 1, Compound 2 and Compound 3, each ofwhich is formulated in amorphous solid dispersion, and the secondcomposition comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first composition comprises 50 mg Compound 1,8.33 mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first composition, and wherein Compound 1, Compound 2 andCompound 3 are each formulated in separate amorphous solid dispersions.The solid dispersion comprising Compound 1 can comprise copovidone,vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound2 can comprise copovidone and vitamin E TPGS; and the solid dispersioncomprising Compound 3 can comprise copovidone and sorbitan monolaurate.These amorphous solid dispersions can be milled and then compressed intothe first composition. The second composition comprises 216.2 mgCompound 4 monosodium salt monohydrate, 30% copovidone, and 30%hypromellose, wherein all percentages are weight percentages relative tothe total weight of the second composition.

In another embodiment, the present invention features a pharmaceuticalsolid dosage form which is a tablet comprising two layers. The firstlayer comprises Compound 1, Compound 2 and Compound 3, each of which isformulated in amorphous solid dispersion, and the second layer comprisesa pharmaceutically acceptable salt of Compound 4 in a crystalline form.The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8%Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer ora combination of pharmaceutically acceptable hydrophilic polymers, and5-10% a pharmaceutically acceptable surfactant or a combination ofpharmaceutically acceptable surfactants, wherein all percentages areweight percentages relative to the total weight of the first layer. Thesecond layer comprises 30-50% a pharmaceutically acceptable salt ofCompound 4, 20-40% a pharmaceutically acceptable stabilizing polymer ora combination of pharmaceutically acceptable stabilizing polymers, and20-40% a pharmaceutically acceptable release rate-modifying polymer or acombination of pharmaceutically acceptable release rate-modifyingpolymers, wherein all percentages are weight percentages relative to thetotal weight of the second layer.

In another embodiment, the present invention features a pharmaceuticalsolid dosage form which is a tablet comprising two layers. The firstlayer comprises Compound 1, Compound 2 and Compound 3, each of which isformulated in amorphous solid dispersion, and the second layer comprisesa pharmaceutically acceptable salt of Compound 4 in a crystalline form.The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mgCompound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer ora combination of pharmaceutically acceptable hydrophilic polymers, and5-10% a pharmaceutically acceptable surfactant or a combination ofpharmaceutically acceptable surfactants, wherein all percentages areweight percentages relative to the total weight of the first layer. Thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4monosodium salt monohydrate), 20-40% a pharmaceutically acceptablestabilizing polymer or a combination of pharmaceutically acceptablestabilizing polymers, and 20-40% a pharmaceutically acceptable releaserate-modifying polymer or a combination of pharmaceutically acceptablerelease rate-modifying polymers, wherein all percentages are weightpercentages relative to the total weight of the second layer.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptablehydrophilic polymer or a combination of pharmaceutically acceptablehydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactantor a combination of pharmaceutically acceptable surfactants, wherein allpercentages are weight percentages relative to the total weight of thefirst layer. The second layer comprises 216.2 mg Compound 4 monosodiumsalt monohydrate, 20-40% a pharmaceutically acceptable stabilizingpolymer or a combination of pharmaceutically acceptable stabilizingpolymers, and 20-40% a pharmaceutically acceptable releaserate-modifying polymer or a combination of pharmaceutically acceptablerelease rate-modifying polymers, wherein all percentages are weightpercentages relative to the total weight of the second layer.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5%Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combinationof vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein allpercentages are weight percentages relative to the total weight of thefirst layer. The second layer comprises 30-50% a pharmaceuticallyacceptable salt of Compound 4, 20-40% copovidone, and 20-40%hypromellose, wherein all percentages are weight percentages relative tothe total weight of the second layer.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, sorbitan monolaurate and lauroglycol,wherein all percentages are weight percentages relative to the totalweight of the first layer. The second layer comprises a pharmaceuticallyacceptable salt of Compound 4 in an amount equivalent to 200 mg Compound4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40%copovidone, and 20-40% hypromellose, wherein all percentages are weightpercentages relative to the total weight of the second layer.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, sorbitan monolaurate and lauroglycol,wherein all percentages are weight percentages relative to the totalweight of the first layer. The second layer comprises 216.2 mg Compound4 monosodium salt monohydrate, 20-40% copovidone, and 20-40%hypromellose, wherein all percentages are weight percentages relative tothe total weight of the second layer.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5%Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combinationof vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein allpercentages are weight percentages relative to the total weight of thefirst layer. The second layer comprises 30-50% a pharmaceuticallyacceptable salt of Compound 4, 30% copovidone, and 30% hypromellose,wherein all percentages are weight percentages relative to the totalweight of the second layer.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, sorbitan monolaurate and lauroglycol,wherein all percentages are weight percentages relative to the totalweight of the first layer. The second layer comprises a pharmaceuticallyacceptable salt of Compound 4 in an amount equivalent to 200 mg Compound4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 30%copovidone, and 30% hypromellose, wherein all percentages are weightpercentages relative to the total weight of the second layer.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, sorbitan monolaurate and lauroglycol,wherein all percentages are weight percentages relative to the totalweight of the first layer. The second layer comprises 216.2 mg Compound4 monosodium salt monohydrate, 30% copovidone, and 30% hypromellose,wherein all percentages are weight percentages relative to the totalweight of the second layer.

In another embodiment, the present invention features a pharmaceuticalsolid dosage form which is a tablet comprising two layers. The firstlayer comprises Compound 1, Compound 2 and Compound 3, each of which isformulated in amorphous solid dispersion, and the second layer comprisesa pharmaceutically acceptable salt of Compound 4 in a crystalline form.The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8%Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer ora combination of pharmaceutically acceptable hydrophilic polymers, and5-10% a pharmaceutically acceptable surfactant or a combination ofpharmaceutically acceptable surfactants, wherein all percentages areweight percentages relative to the total weight of the first layer, andwherein Compound 1, Compound 2 and Compound 3 are formulated in the sameamorphous solid dispersion which comprises (1) the hydrophilic polymeror the combination of hydrophilic polymers and (2) the surfactant or thecombination of surfactants. The amorphous solid dispersion can be milledand compressed into the first layer. The second layer comprises 30-50% apharmaceutically acceptable salt of Compound 4, 20-40% apharmaceutically acceptable stabilizing polymer or a combination ofpharmaceutically acceptable stabilizing polymers, and 20-40% apharmaceutically acceptable release rate-modifying polymer or acombination of pharmaceutically acceptable release rate-modifyingpolymers, wherein all percentages are weight percentages relative to thetotal weight of the second layer.

In another embodiment, the present invention features a pharmaceuticalsolid dosage form which is a tablet comprising two layers. The firstlayer comprises Compound 1, Compound 2 and Compound 3, each of which isformulated in amorphous solid dispersion, and the second layer comprisesa pharmaceutically acceptable salt of Compound 4 in a crystalline form.The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mgCompound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer ora combination of pharmaceutically acceptable hydrophilic polymers, and5-10% a pharmaceutically acceptable surfactant or a combination ofpharmaceutically acceptable surfactants, wherein all percentages areweight percentages relative to the total weight of the first layer, andwherein Compound 1, Compound 2 and Compound 3 are formulated in the sameamorphous solid dispersion which comprises (1) the hydrophilic polymeror the combination of hydrophilic polymers and (2) the surfactant or thecombination of surfactants. The amorphous solid dispersion can be milledand compressed into the first layer. The second layer comprises apharmaceutically acceptable salt of Compound 4 in an amount equivalentto 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium saltmonohydrate), 20-40% a pharmaceutically acceptable stabilizing polymeror a combination of pharmaceutically acceptable stabilizing polymers,and 20-40% a pharmaceutically acceptable release rate-modifying polymeror a combination of pharmaceutically acceptable release rate-modifyingpolymers, wherein all percentages are weight percentages relative to thetotal weight of the second layer.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptablehydrophilic polymer or a combination of pharmaceutically acceptablehydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactantor a combination of pharmaceutically acceptable surfactants, wherein allpercentages are weight percentages relative to the total weight of thefirst layer, and wherein Compound 1, Compound 2 and Compound 3 areformulated in the same amorphous solid dispersion which comprises (1)the hydrophilic polymer or the combination of hydrophilic polymers and(2) the surfactant or the combination of surfactants. The amorphoussolid dispersion can be milled and compressed into the first layer. Thesecond layer comprises 216.2 mg Compound 4 monosodium salt monohydrate,20-40% a pharmaceutically acceptable stabilizing polymer or acombination of pharmaceutically acceptable stabilizing polymers, and20-40% a pharmaceutically acceptable release rate-modifying polymer or acombination of pharmaceutically acceptable release rate-modifyingpolymers, wherein all percentages are weight percentages relative to thetotal weight of the second layer.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5%Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combinationof vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein allpercentages are weight percentages relative to the total weight of thefirst layer, and wherein Compound 1, Compound 2 and Compound 3 areformulated in the same amorphous solid dispersion which comprisescopovidone, vitamin E TPGS, lauroglycol and sorbitan monolaurate. Theamorphous solid dispersion can be milled and compressed into the firstlayer. The second layer comprises 30-50% a pharmaceutically acceptablesalt of Compound 4, 20-40% copovidone, and 20-40% hypromellose, whereinall percentages are weight percentages relative to the total weight ofthe second layer.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first layer, and wherein Compound 1, Compound 2 andCompound 3 are formulated in the same amorphous solid dispersion whichcomprises copovidone, vitamin E TPGS, lauroglycol and sorbitanmonolaurate. The amorphous solid dispersion can be milled and compressedinto the first layer. The second layer comprises a pharmaceuticallyacceptable salt of Compound 4 in an amount equivalent to 200 mg Compound4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40%copovidone, and 20-40% hypromellose, wherein all percentages are weightpercentages relative to the total weight of the second layer.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first layer, and wherein Compound 1, Compound 2 andCompound 3 are formulated in the same amorphous solid dispersion whichcomprises copovidone, vitamin E TPGS, lauroglycol and sorbitanmonolaurate. The amorphous solid dispersion can be milled and compressedinto the first layer. The second layer comprises 216.2 mg Compound 4monosodium salt monohydrate, 20-40% copovidone, and 20-40% hypromellose,wherein all percentages are weight percentages relative to the totalweight of the second layer.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5%Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combinationof vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein allpercentages are weight percentages relative to the total weight of thefirst layer, and wherein Compound 1, Compound 2 and Compound 3 areformulated in the same amorphous solid dispersion which comprisescopovidone, vitamin E TPGS, lauroglycol and sorbitan monolaurate. Theamorphous solid dispersion can be milled and compressed into the firstlayer. The second layer comprises 30-50% a pharmaceutically acceptablesalt of Compound 4, 30% copovidone, and 30% hypromellose, wherein allpercentages are weight percentages relative to the total weight of thesecond layer.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first layer, and wherein Compound 1, Compound 2 andCompound 3 are formulated in the same amorphous solid dispersion whichcomprises copovidone, vitamin E TPGS, lauroglycol and sorbitanmonolaurate. The amorphous solid dispersion can be milled and compressedinto the first layer. The second layer comprises a pharmaceuticallyacceptable salt of Compound 4 in an amount equivalent to 200 mg Compound4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 30%copovidone, and 30% hypromellose, wherein all percentages are weightpercentages relative to the total weight of the second layer.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first layer, and wherein Compound 1, Compound 2 andCompound 3 are formulated in the same amorphous solid dispersion whichcomprises copovidone, vitamin E TPGS, lauroglycol and sorbitanmonolaurate. The amorphous solid dispersion can be milled and compressedinto the first layer. The second layer comprises 216.2 mg Compound 4monosodium salt monohydrate, 30% copovidone, and 30% hypromellose,wherein all percentages are weight percentages relative to the totalweight of the second layer.

In another embodiment, the present invention features a pharmaceuticalsolid dosage form which is a tablet comprising two layers. The firstlayer comprises Compound 1, Compound 2 and Compound 3, each of which isformulated in amorphous solid dispersion, and the second layer comprisesa pharmaceutically acceptable salt of Compound 4 in a crystalline form.The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8%Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer ora combination of pharmaceutically acceptable hydrophilic polymers, and5-10% a pharmaceutically acceptable surfactant or a combination ofpharmaceutically acceptable surfactants, wherein all percentages areweight percentages relative to the total weight of the first layer, andwherein Compound 1, Compound 2 and Compound 3 are each formulated inseparate amorphous solid dispersions, and each solid dispersioncomprises (1) the hydrophilic polymer or the combination of hydrophilicpolymers and (2) the surfactant or one of the combination ofsurfactants. These amorphous solid dispersions can be milled and thencompressed into the first layer. The second layer comprises 30-50% apharmaceutically acceptable salt of Compound 4, 20-40% apharmaceutically acceptable stabilizing polymer or a combination ofpharmaceutically acceptable stabilizing polymers, and 20-40% apharmaceutically acceptable release rate-modifying polymer or acombination of pharmaceutically acceptable release rate-modifyingpolymers, wherein all percentages are weight percentages relative to thetotal weight of the second layer.

In another embodiment, the present invention features a pharmaceuticalsolid dosage form which is a tablet comprising two layers. The firstlayer comprises Compound 1, Compound 2 and Compound 3, each of which isformulated in amorphous solid dispersion, and the second layer comprisesa pharmaceutically acceptable salt of Compound 4 in a crystalline form.The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mgCompound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer ora combination of pharmaceutically acceptable hydrophilic polymers, and5-10% a pharmaceutically acceptable surfactant or a combination ofpharmaceutically acceptable surfactants, wherein all percentages areweight percentages relative to the total weight of the first layer, andwherein Compound 1, Compound 2 and Compound 3 are each formulated inseparate amorphous solid dispersions, and each solid dispersioncomprises (1) the hydrophilic polymer or one of the combination ofhydrophilic polymers and (2) the surfactant or one of the combination ofsurfactants. These amorphous solid dispersions can be milled and thencompressed into the first layer. The second layer comprises apharmaceutically acceptable salt of Compound 4 in an amount equivalentto 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium saltmonohydrate), 20-40% a pharmaceutically acceptable stabilizing polymeror a combination of pharmaceutically acceptable stabilizing polymers,and 20-40% a pharmaceutically acceptable release rate-modifying polymeror a combination of pharmaceutically acceptable release rate-modifyingpolymers, wherein all percentages are weight percentages relative to thetotal weight of the second layer.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptablehydrophilic polymer or a combination of pharmaceutically acceptablehydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactantor a combination of pharmaceutically acceptable surfactants, wherein allpercentages are weight percentages relative to the total weight of thefirst layer, and wherein Compound 1, Compound 2 and Compound 3 are eachformulated in separate amorphous solid dispersions, and each soliddispersion comprises (1) the hydrophilic polymer or one of thecombination of hydrophilic polymers and (2) the surfactant or one of thecombination of surfactants. These amorphous solid dispersions can bemilled and then compressed into the first layer. The second layercomprises 216.2 mg Compound 4 monosodium salt monohydrate, 20-40% apharmaceutically acceptable stabilizing polymer or a combination ofpharmaceutically acceptable stabilizing polymers, and 20-40% apharmaceutically acceptable release rate-modifying polymer or acombination of pharmaceutically acceptable release rate-modifyingpolymers, wherein all percentages are weight percentages relative to thetotal weight of the second layer.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5%Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combinationof vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein allpercentages are weight percentages relative to the total weight of thefirst layer, and wherein Compound 1, Compound 2 and Compound 3 are eachformulated in separate amorphous solid dispersions. The solid dispersioncomprising Compound 1 can comprise copovidone, vitamin E TPGS andlauroglycol; the solid dispersion comprising Compound 2 can comprisecopovidone and vitamin E TPGS; and the solid dispersion comprisingCompound 3 can comprise copovidone and sorbitan monolaurate. Theseamorphous solid dispersions can be milled and then compressed into thefirst layer. The second layer comprises 30-50% a pharmaceuticallyacceptable salt of Compound 4, 20-40% copovidone, and 20-40%hypromellose, wherein all percentages are weight percentages relative tothe total weight of the second layer.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first layer, and wherein Compound 1, Compound 2 andCompound 3 are each formulated in separate amorphous solid dispersions.The solid dispersion comprising Compound 1 can comprise copovidone,vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound2 can comprise copovidone and vitamin E TPGS; and the solid dispersioncomprising Compound 3 can comprise copovidone and sorbitan monolaurate.These amorphous solid dispersions can be milled and then compressed intothe first layer. The second layer comprises a pharmaceuticallyacceptable salt of Compound 4 in an amount equivalent to 200 mg Compound4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40%copovidone, and 20-40% hypromellose, wherein all percentages are weightpercentages relative to the total weight of the second layer.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first layer, and wherein Compound 1, Compound 2 andCompound 3 are each formulated in separate amorphous solid dispersions.The solid dispersion comprising Compound 1 can comprise copovidone,vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound2 can comprise copovidone and vitamin E TPGS; and the solid dispersioncomprising Compound 3 can comprise copovidone and sorbitan monolaurate.These amorphous solid dispersions can be milled and then compressed intothe first layer. The second layer comprises 216.2 mg Compound 4monosodium salt monohydrate, 20-40% copovidone, and 20-40% hypromellose,wherein all percentages are weight percentages relative to the totalweight of the second layer.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5%Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combinationof vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein allpercentages are weight percentages relative to the total weight of thefirst layer, and wherein Compound 1, Compound 2 and Compound 3 are eachformulated in separate amorphous solid dispersions. The solid dispersioncomprising Compound 1 can comprise copovidone, vitamin E TPGS andlauroglycol; the solid dispersion comprising Compound 2 can comprisecopovidone and vitamin E TPGS; and the solid dispersion comprisingCompound 3 can comprise copovidone and sorbitan monolaurate. Theseamorphous solid dispersions can be milled and then compressed into thefirst layer. The second layer comprises 30-50% a pharmaceuticallyacceptable salt of Compound 4, 30% copovidone, and 30% hypromellose,wherein all percentages are weight percentages relative to the totalweight of the second layer.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first layer, and wherein Compound 1, Compound 2 andCompound 3 are each formulated in separate amorphous solid dispersions.The solid dispersion comprising Compound 1 can comprise copovidone,vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound2 can comprise copovidone and vitamin E TPGS; and the solid dispersioncomprising Compound 3 can comprise copovidone and sorbitan monolaurate.These amorphous solid dispersions can be milled and then compressed intothe first layer. The second layer comprises a pharmaceuticallyacceptable salt of Compound 4 in an amount equivalent to 200 mg Compound4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 30%copovidone, and 30% hypromellose, wherein all percentages are weightpercentages relative to the total weight of the second layer.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first layer, and wherein Compound 1, Compound 2 andCompound 3 are each formulated in separate amorphous solid dispersions.The solid dispersion comprising Compound 1 can comprise copovidone,vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound2 can comprise copovidone and vitamin E TPGS; and the solid dispersioncomprising Compound 3 can comprise copovidone and sorbitan monolaurate.These amorphous solid dispersions can be milled and then compressed intothe first layer. The second layer comprises 216.2 mg Compound 4monosodium salt monohydrate, 30% copovidone, and 30% hypromellose,wherein all percentages are weight percentages relative to the totalweight of the second layer.

In each and every embodiment, aspect and example described herein, whenthe pharmaceutical solid dosage form is dissolved in 900 mL of adissolution medium using a standard USP dissolution Apparatus 2 (paddle)operating at 100 RPM at 37° C., the solid dosage form can, for example,have the following release profile: 50-60% Compound 1 in the soliddosage form is released within 1 hour, 50-60% Compound 2 in the soliddosage form is released within 1 hour, 50-60% Compound 3 in the soliddosage form is released within 1 hour, and 0.5-2% Compound 4 in thesolid dosage form is released within 1 hour. The dissolution medium is0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.

In each and every embodiment, aspect and example described herein, whenthe pharmaceutical solid dosage form is dissolved in 900 mL of adissolution medium using a standard USP dissolution Apparatus 2 (paddle)operating at 100 RPM at 37° C., the solid dosage form can, for example,have the following release profile: 95-100% Compound 1 in the soliddosage form is released within 4 hours, 95-100% Compound 2 in the soliddosage form is released within 4 hours, 95-100% Compound 3 in the soliddosage form is released within 4 hours, and 10-15% Compound 4 in thesolid dosage form is released within 4 hours. The dissolution medium is0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.

In each and every embodiment, aspect and example described herein, whenthe pharmaceutical solid dosage form is dissolved in 900 mL of adissolution medium using a standard USP dissolution Apparatus 2 (paddle)operating at 100 RPM at 37° C., the solid dosage form can, for example,have the following release profile: 95-100% Compound 1 in the soliddosage form is released within 6 hours, 95-100% Compound 2 in the soliddosage form is released within 6 hours, 95-100% Compound 3 in the soliddosage form is released within 6 hours, and 15-20% Compound 4 in thesolid dosage form is released within 6 hours. The dissolution medium is0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.

In each and every embodiment, aspect and example described herein, whenthe pharmaceutical solid dosage form is dissolved in 900 mL of adissolution medium using a standard USP dissolution Apparatus 2 (paddle)operating at 100 RPM at 37° C., the solid dosage form can, for example,have the following release profile: 100% Compound 1 in the solid dosageform is released within 8 hours, 100% Compound 2 in the solid dosageform is released within 8 hours, 100% Compound 3 in the solid dosageform is released within 8 hours, 20-30% Compound 4 in the solid dosageform is released within 8 hours, 30-40% Compound 4 in the solid dosageform is released within 12 hours, and 40-60% Compound 4 in the soliddosage form is released within 16 hours. The dissolution medium is 0.05M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.

In each and every embodiment, aspect and example described herein, whenthe pharmaceutical solid dosage form is dissolved in 900 mL of adissolution medium using a standard USP dissolution Apparatus 2 (paddle)operating at 100 RPM at 37° C., the solid dosage form can, for example,have the following release profile: 100% Compound 1 in the solid dosageform is released within 8 hours, 100% Compound 2 in the solid dosageform is released within 8 hours, 100% Compound 3 in the solid dosageform is released within 8 hours, 20-30% Compound 4 in the solid dosageform is released within 8 hours, 30-40% Compound 4 in the solid dosageform is released within 12 hours, 40-60% Compound 4 in the solid dosageform is released within 16 hours, and 60-80% Compound 4 in the soliddosage form is released within 24 hours. The dissolution medium is 0.05M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.

Accordingly, in another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5%Compound 2, 2-8% Compound 3, 70-85% a pharmaceutically acceptablehydrophilic polymer or a combination of pharmaceutically acceptablehydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactantor a combination of pharmaceutically acceptable surfactants, wherein allpercentages are weight percentages relative to the total weight of thefirst layer. The second layer comprises 30-50% a pharmaceuticallyacceptable salt of Compound 4, 20-40% a pharmaceutically acceptablestabilizing polymer or a combination of pharmaceutically acceptablestabilizing polymers, and 20-40% a pharmaceutically acceptable releaserate-modifying polymer or a combination of pharmaceutically acceptablerelease rate-modifying polymers, wherein all percentages are weightpercentages relative to the total weight of the second layer. When thepharmaceutical solid dosage form is dissolved in 900 mL of a dissolutionmedium using a standard USP dissolution Apparatus 2 (paddle) operatingat 100 RPM at 37° C., the solid dosage form can have the followingrelease profile: 100% Compound 1 in the solid dosage form is releasedwithin 8 hours, 100% Compound 2 in the solid dosage form is releasedwithin 8 hours, 100% Compound 3 in the solid dosage form is releasedwithin 8 hours, 20-30% Compound 4 in the solid dosage form is releasedwithin 8 hours, 30-40% Compound 4 in the solid dosage form is releasedwithin 12 hours, 40-60% Compound 4 in the solid dosage form is releasedwithin 16 hours, and 60-80% Compound 4 in the solid dosage form isreleased within 24 hours. The dissolution medium is 0.05 M sodiumphosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.

In another embodiment, the present invention features a pharmaceuticalsolid dosage form which is a tablet comprising two layers. The firstlayer comprises Compound 1, Compound 2 and Compound 3, each of which isformulated in amorphous solid dispersion, and the second layer comprisesa pharmaceutically acceptable salt of Compound 4 in a crystalline form.The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mgCompound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer ora combination of pharmaceutically acceptable hydrophilic polymers, and5-10% a pharmaceutically acceptable surfactant or a combination ofpharmaceutically acceptable surfactants, wherein all percentages areweight percentages relative to the total weight of the first layer. Thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4monosodium salt monohydrate), 20-40% a pharmaceutically acceptablestabilizing polymer or a combination of pharmaceutically acceptablestabilizing polymers, and 20-40% a pharmaceutically acceptable releaserate-modifying polymer or a combination of pharmaceutically acceptablerelease rate-modifying polymers, wherein all percentages are weightpercentages relative to the total weight of the second layer. When thepharmaceutical solid dosage form is dissolved in 900 mL of a dissolutionmedium using a standard USP dissolution Apparatus 2 (paddle) operatingat 100 RPM at 37° C., the solid dosage form can have the followingrelease profile: 100% Compound 1 in the solid dosage form is releasedwithin 8 hours, 100% Compound 2 in the solid dosage form is releasedwithin 8 hours, 100% Compound 3 in the solid dosage form is releasedwithin 8 hours, 20-30% Compound 4 in the solid dosage form is releasedwithin 8 hours, 30-40% Compound 4 in the solid dosage form is releasedwithin 12 hours, 40-60% Compound 4 in the solid dosage form is releasedwithin 16 hours, and 60-80% Compound 4 in the solid dosage form isreleased within 24 hours. The dissolution medium is 0.05 M sodiumphosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptablehydrophilic polymer or a combination of pharmaceutically acceptablehydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactantor a combination of pharmaceutically acceptable surfactants, wherein allpercentages are weight percentages relative to the total weight of thefirst layer. The second layer comprises 216.2 mg Compound 4 monosodiumsalt monohydrate, 20-40% a pharmaceutically acceptable stabilizingpolymer or a combination of pharmaceutically acceptable stabilizingpolymers, and 20-40% a pharmaceutically acceptable releaserate-modifying polymer or a combination of pharmaceutically acceptablerelease rate-modifying polymers, wherein all percentages are weightpercentages relative to the total weight of the second layer. When thepharmaceutical solid dosage form is dissolved in 900 mL of a dissolutionmedium using a standard USP dissolution Apparatus 2 (paddle) operatingat 100 RPM at 37° C., the solid dosage form can have the followingrelease profile: 100% Compound 1 in the solid dosage form is releasedwithin 8 hours, 100% Compound 2 in the solid dosage form is releasedwithin 8 hours, 100% Compound 3 in the solid dosage form is releasedwithin 8 hours, 20-30% Compound 4 in the solid dosage form is releasedwithin 8 hours, 30-40% Compound 4 in the solid dosage form is releasedwithin 12 hours, 40-60% Compound 4 in the solid dosage form is releasedwithin 16 hours, and 60-80% Compound 4 in the solid dosage form isreleased within 24 hours. The dissolution medium is 0.05 M sodiumphosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5%Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combinationof vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein allpercentages are weight percentages relative to the total weight of thefirst layer. The second layer comprises 30-50% a pharmaceuticallyacceptable salt of Compound 4, 20-40% copovidone, and 20-40%hypromellose, wherein all percentages are weight percentages relative tothe total weight of the second layer. When the pharmaceutical soliddosage form is dissolved in 900 mL of a dissolution medium using astandard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at37° C., the solid dosage form can have the following release profile:100% Compound 1 in the solid dosage form is released within 8 hours,100% Compound 2 in the solid dosage form is released within 8 hours,100% Compound 3 in the solid dosage form is released within 8 hours,20-30% Compound 4 in the solid dosage form is released within 8 hours,30-40% Compound 4 in the solid dosage form is released within 12 hours,40-60% Compound 4 in the solid dosage form is released within 16 hours,and 60-80% Compound 4 in the solid dosage form is released within 24hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8)with 15 mM cTAB as a surfactant.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, sorbitan monolaurate and lauroglycol,wherein all percentages are weight percentages relative to the totalweight of the first layer. The second layer comprises a pharmaceuticallyacceptable salt of Compound 4 in an amount equivalent to 200 mg Compound4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40%copovidone, and 20-40% hypromellose, wherein all percentages are weightpercentages relative to the total weight of the second layer. When thepharmaceutical solid dosage form is dissolved in 900 mL of a dissolutionmedium using a standard USP dissolution Apparatus 2 (paddle) operatingat 100 RPM at 37° C., the solid dosage form can have the followingrelease profile: 100% Compound 1 in the solid dosage form is releasedwithin 8 hours, 100% Compound 2 in the solid dosage form is releasedwithin 8 hours, 100% Compound 3 in the solid dosage form is releasedwithin 8 hours, 20-30% Compound 4 in the solid dosage form is releasedwithin 8 hours, 30-40% Compound 4 in the solid dosage form is releasedwithin 12 hours, 40-60% Compound 4 in the solid dosage form is releasedwithin 16 hours, and 60-80% Compound 4 in the solid dosage form isreleased within 24 hours. The dissolution medium is 0.05 M sodiumphosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, sorbitan monolaurate and lauroglycol,wherein all percentages are weight percentages relative to the totalweight of the first layer. The second layer comprises 216.2 mg Compound4 monosodium salt monohydrate, 20-40% copovidone, and 20-40%hypromellose, wherein all percentages are weight percentages relative tothe total weight of the second layer. When the pharmaceutical soliddosage form is dissolved in 900 mL of a dissolution medium using astandard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at37° C., the solid dosage form can have the following release profile:100% Compound 1 in the solid dosage form is released within 8 hours,100% Compound 2 in the solid dosage form is released within 8 hours,100% Compound 3 in the solid dosage form is released within 8 hours,20-30% Compound 4 in the solid dosage form is released within 8 hours,30-40% Compound 4 in the solid dosage form is released within 12 hours,40-60% Compound 4 in the solid dosage form is released within 16 hours,and 60-80% Compound 4 in the solid dosage form is released within 24hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8)with 15 mM cTAB as a surfactant.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5%Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combinationof vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein allpercentages are weight percentages relative to the total weight of thefirst layer. The second layer comprises 30-50% a pharmaceuticallyacceptable salt of Compound 4, 30% copovidone, and 30% hypromellose,wherein all percentages are weight percentages relative to the totalweight of the second layer. When the pharmaceutical solid dosage form isdissolved in 900 mL of a dissolution medium using a standard USPdissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., thesolid dosage form can have the following release profile: 100% Compound1 in the solid dosage form is released within 8 hours, 100% Compound 2in the solid dosage form is released within 8 hours, 100% Compound 3 inthe solid dosage form is released within 8 hours, 20-30% Compound 4 inthe solid dosage form is released within 8 hours, 30-40% Compound 4 inthe solid dosage form is released within 12 hours, 40-60% Compound 4 inthe solid dosage form is released within 16 hours, and 60-80% Compound 4in the solid dosage form is released within 24 hours. The dissolutionmedium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as asurfactant.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, sorbitan monolaurate and lauroglycol,wherein all percentages are weight percentages relative to the totalweight of the first layer. The second layer comprises a pharmaceuticallyacceptable salt of Compound 4 in an amount equivalent to 200 mg Compound4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 30%copovidone, and 30% hypromellose, wherein all percentages are weightpercentages relative to the total weight of the second layer. When thepharmaceutical solid dosage form is dissolved in 900 mL of a dissolutionmedium using a standard USP dissolution Apparatus 2 (paddle) operatingat 100 RPM at 37° C., the solid dosage form can have the followingrelease profile: 100% Compound 1 in the solid dosage form is releasedwithin 8 hours, 100% Compound 2 in the solid dosage form is releasedwithin 8 hours, 100% Compound 3 in the solid dosage form is releasedwithin 8 hours, 20-30% Compound 4 in the solid dosage form is releasedwithin 8 hours, 30-40% Compound 4 in the solid dosage form is releasedwithin 12 hours, 40-60% Compound 4 in the solid dosage form is releasedwithin 16 hours, and 60-80% Compound 4 in the solid dosage form isreleased within 24 hours. The dissolution medium is 0.05 M sodiumphosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, sorbitan monolaurate and lauroglycol,wherein all percentages are weight percentages relative to the totalweight of the first layer. The second layer comprises 216.2 mg Compound4 monosodium salt monohydrate, 30% copovidone, and 30% hypromellose,wherein all percentages are weight percentages relative to the totalweight of the second layer. When the pharmaceutical solid dosage form isdissolved in 900 mL of a dissolution medium using a standard USPdissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., thesolid dosage form can have the following release profile: 100% Compound1 in the solid dosage form is released within 8 hours, 100% Compound 2in the solid dosage form is released within 8 hours, 100% Compound 3 inthe solid dosage form is released within 8 hours, 20-30% Compound 4 inthe solid dosage form is released within 8 hours, 30-40% Compound 4 inthe solid dosage form is released within 12 hours, 40-60% Compound 4 inthe solid dosage form is released within 16 hours, and 60-80% Compound 4in the solid dosage form is released within 24 hours. The dissolutionmedium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as asurfactant.

In another embodiment, the present invention features a pharmaceuticalsolid dosage form which is a tablet comprising two layers. The firstlayer comprises Compound 1, Compound 2 and Compound 3, each of which isformulated in amorphous solid dispersion, and the second layer comprisesa pharmaceutically acceptable salt of Compound 4 in a crystalline form.The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8%Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer ora combination of pharmaceutically acceptable hydrophilic polymers, and5-10% a pharmaceutically acceptable surfactant or a combination ofpharmaceutically acceptable surfactants, wherein all percentages areweight percentages relative to the total weight of the first layer, andwherein Compound 1, Compound 2 and Compound 3 are formulated in the sameamorphous solid dispersion which comprises (1) the hydrophilic polymeror the combination of hydrophilic polymers and (2) the surfactant or thecombination of surfactants. The amorphous solid dispersion can be milledand compressed into the first layer. The second layer comprises 30-50% apharmaceutically acceptable salt of Compound 4, 20-40% apharmaceutically acceptable stabilizing polymer or a combination ofpharmaceutically acceptable stabilizing polymers, and 20-40% apharmaceutically acceptable release rate-modifying polymer or acombination of pharmaceutically acceptable release rate-modifyingpolymers, wherein all percentages are weight percentages relative to thetotal weight of the second layer. When the pharmaceutical solid dosageform is dissolved in 900 mL of a dissolution medium using a standard USPdissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., thesolid dosage form can have the following release profile: 100% Compound1 in the solid dosage form is released within 8 hours, 100% Compound 2in the solid dosage form is released within 8 hours, 100% Compound 3 inthe solid dosage form is released within 8 hours, 20-30% Compound 4 inthe solid dosage form is released within 8 hours, 30-40% Compound 4 inthe solid dosage form is released within 12 hours, 40-60% Compound 4 inthe solid dosage form is released within 16 hours, and 60-80% Compound 4in the solid dosage form is released within 24 hours. The dissolutionmedium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as asurfactant.

In another embodiment, the present invention features a pharmaceuticalsolid dosage form which is a tablet comprising two layers. The firstlayer comprises Compound 1, Compound 2 and Compound 3, each of which isformulated in amorphous solid dispersion, and the second layer comprisesa pharmaceutically acceptable salt of Compound 4 in a crystalline form.The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mgCompound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer ora combination of pharmaceutically acceptable hydrophilic polymers, and5-10% a pharmaceutically acceptable surfactant or a combination ofpharmaceutically acceptable surfactants, wherein all percentages areweight percentages relative to the total weight of the first layer, andwherein Compound 1, Compound 2 and Compound 3 are formulated in the sameamorphous solid dispersion which comprises (1) the hydrophilic polymeror the combination of hydrophilic polymers and (2) the surfactant or thecombination of surfactants. The amorphous solid dispersion can be milledand compressed into the first layer. The second layer comprises apharmaceutically acceptable salt of Compound 4 in an amount equivalentto 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium saltmonohydrate), 20-40% a pharmaceutically acceptable stabilizing polymeror a combination of pharmaceutically acceptable stabilizing polymers,and 20-40% a pharmaceutically acceptable release rate-modifying polymeror a combination of pharmaceutically acceptable release rate-modifyingpolymers, wherein all percentages are weight percentages relative to thetotal weight of the second layer. When the pharmaceutical solid dosageform is dissolved in 900 mL of a dissolution medium using a standard USPdissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., thesolid dosage form can have the following release profile: 100% Compound1 in the solid dosage form is released within 8 hours, 100% Compound 2in the solid dosage form is released within 8 hours, 100% Compound 3 inthe solid dosage form is released within 8 hours, 20-30% Compound 4 inthe solid dosage form is released within 8 hours, 30-40% Compound 4 inthe solid dosage form is released within 12 hours, 40-60% Compound 4 inthe solid dosage form is released within 16 hours, and 60-80% Compound 4in the solid dosage form is released within 24 hours. The dissolutionmedium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as asurfactant.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptablehydrophilic polymer or a combination of pharmaceutically acceptablehydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactantor a combination of pharmaceutically acceptable surfactants, wherein allpercentages are weight percentages relative to the total weight of thefirst layer, and wherein Compound 1, Compound 2 and Compound 3 areformulated in the same amorphous solid dispersion which comprises (1)the hydrophilic polymer or the combination of hydrophilic polymers and(2) the surfactant or the combination of surfactants. The amorphoussolid dispersion can be milled and compressed into the first layer. Thesecond layer comprises 216.2 mg Compound 4 monosodium salt monohydrate,20-40% a pharmaceutically acceptable stabilizing polymer or acombination of pharmaceutically acceptable stabilizing polymers, and20-40% a pharmaceutically acceptable release rate-modifying polymer or acombination of pharmaceutically acceptable release rate-modifyingpolymers, wherein all percentages are weight percentages relative to thetotal weight of the second layer. When the pharmaceutical solid dosageform is dissolved in 900 mL of a dissolution medium using a standard USPdissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., thesolid dosage form can have the following release profile: 100% Compound1 in the solid dosage form is released within 8 hours, 100% Compound 2in the solid dosage form is released within 8 hours, 100% Compound 3 inthe solid dosage form is released within 8 hours, 20-30% Compound 4 inthe solid dosage form is released within 8 hours, 30-40% Compound 4 inthe solid dosage form is released within 12 hours, 40-60% Compound 4 inthe solid dosage form is released within 16 hours, and 60-80% Compound 4in the solid dosage form is released within 24 hours. The dissolutionmedium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as asurfactant.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5%Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combinationof vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein allpercentages are weight percentages relative to the total weight of thefirst layer, and wherein Compound 1, Compound 2 and Compound 3 areformulated in the same amorphous solid dispersion which comprisescopovidone, vitamin E TPGS, lauroglycol and sorbitan monolaurate. Theamorphous solid dispersion can be milled and compressed into the firstlayer. The second layer comprises 30-50% a pharmaceutically acceptablesalt of Compound 4, 20-40% copovidone, and 20-40% hypromellose, whereinall percentages are weight percentages relative to the total weight ofthe second layer. When the pharmaceutical solid dosage form is dissolvedin 900 mL of a dissolution medium using a standard USP dissolutionApparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosageform can have the following release profile: 100% Compound 1 in thesolid dosage form is released within 8 hours, 100% Compound 2 in thesolid dosage form is released within 8 hours, 100% Compound 3 in thesolid dosage form is released within 8 hours, 20-30% Compound 4 in thesolid dosage form is released within 8 hours, 30-40% Compound 4 in thesolid dosage form is released within 12 hours, 40-60% Compound 4 in thesolid dosage form is released within 16 hours, and 60-80% Compound 4 inthe solid dosage form is released within 24 hours. The dissolutionmedium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as asurfactant.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first layer, and wherein Compound 1, Compound 2 andCompound 3 are formulated in the same amorphous solid dispersion whichcomprises copovidone, vitamin E TPGS, lauroglycol and sorbitanmonolaurate. The amorphous solid dispersion can be milled and compressedinto the first layer. The second layer comprises a pharmaceuticallyacceptable salt of Compound 4 in an amount equivalent to 200 mg Compound4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40%copovidone, and 20-40% hypromellose, wherein all percentages are weightpercentages relative to the total weight of the second layer. When thepharmaceutical solid dosage form is dissolved in 900 mL of a dissolutionmedium using a standard USP dissolution Apparatus 2 (paddle) operatingat 100 RPM at 37° C., the solid dosage form can have the followingrelease profile: 100% Compound 1 in the solid dosage form is releasedwithin 8 hours, 100% Compound 2 in the solid dosage form is releasedwithin 8 hours, 100% Compound 3 in the solid dosage form is releasedwithin 8 hours, 20-30% Compound 4 in the solid dosage form is releasedwithin 8 hours, 30-40% Compound 4 in the solid dosage form is releasedwithin 12 hours, 40-60% Compound 4 in the solid dosage form is releasedwithin 16 hours, and 60-80% Compound 4 in the solid dosage form isreleased within 24 hours. The dissolution medium is 0.05 M sodiumphosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first layer, and wherein Compound 1, Compound 2 andCompound 3 are formulated in the same amorphous solid dispersion whichcomprises copovidone, vitamin E TPGS, lauroglycol and sorbitanmonolaurate. The amorphous solid dispersion can be milled and compressedinto the first layer. The second layer comprises 216.2 mg Compound 4monosodium salt monohydrate, 20-40% copovidone, and 20-40% hypromellose,wherein all percentages are weight percentages relative to the totalweight of the second layer. When the pharmaceutical solid dosage form isdissolved in 900 mL of a dissolution medium using a standard USPdissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., thesolid dosage form can have the following release profile: 100% Compound1 in the solid dosage form is released within 8 hours, 100% Compound 2in the solid dosage form is released within 8 hours, 100% Compound 3 inthe solid dosage form is released within 8 hours, 20-30% Compound 4 inthe solid dosage form is released within 8 hours, 30-40% Compound 4 inthe solid dosage form is released within 12 hours, 40-60% Compound 4 inthe solid dosage form is released within 16 hours, and 60-80% Compound 4in the solid dosage form is released within 24 hours. The dissolutionmedium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as asurfactant.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5%Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combinationof vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein allpercentages are weight percentages relative to the total weight of thefirst layer, and wherein Compound 1, Compound 2 and Compound 3 areformulated in the same amorphous solid dispersion which comprisescopovidone, vitamin E TPGS, lauroglycol and sorbitan monolaurate. Theamorphous solid dispersion can be milled and compressed into the firstlayer. The second layer comprises 30-50% a pharmaceutically acceptablesalt of Compound 4, 30% copovidone, and 30% hypromellose, wherein allpercentages are weight percentages relative to the total weight of thesecond layer. When the pharmaceutical solid dosage form is dissolved in900 mL of a dissolution medium using a standard USP dissolutionApparatus 2 (paddle) operating at 100 RPM at 37° C., the solid dosageform can have the following release profile: 100% Compound 1 in thesolid dosage form is released within 8 hours, 100% Compound 2 in thesolid dosage form is released within 8 hours, 100% Compound 3 in thesolid dosage form is released within 8 hours, 20-30% Compound 4 in thesolid dosage form is released within 8 hours, 30-40% Compound 4 in thesolid dosage form is released within 12 hours, 40-60% Compound 4 in thesolid dosage form is released within 16 hours, and 60-80% Compound 4 inthe solid dosage form is released within 24 hours. The dissolutionmedium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as asurfactant.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first layer, and wherein Compound 1, Compound 2 andCompound 3 are formulated in the same amorphous solid dispersion whichcomprises copovidone, vitamin E TPGS, lauroglycol and sorbitanmonolaurate. The amorphous solid dispersion can be milled and compressedinto the first layer. The second layer comprises a pharmaceuticallyacceptable salt of Compound 4 in an amount equivalent to 200 mg Compound4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 30%copovidone, and 30% hypromellose, wherein all percentages are weightpercentages relative to the total weight of the second layer. When thepharmaceutical solid dosage form is dissolved in 900 mL of a dissolutionmedium using a standard USP dissolution Apparatus 2 (paddle) operatingat 100 RPM at 37° C., the solid dosage form can have the followingrelease profile: 100% Compound 1 in the solid dosage form is releasedwithin 8 hours, 100% Compound 2 in the solid dosage form is releasedwithin 8 hours, 100% Compound 3 in the solid dosage form is releasedwithin 8 hours, 20-30% Compound 4 in the solid dosage form is releasedwithin 8 hours, 30-40% Compound 4 in the solid dosage form is releasedwithin 12 hours, 40-60% Compound 4 in the solid dosage form is releasedwithin 16 hours, and 60-80% Compound 4 in the solid dosage form isreleased within 24 hours. The dissolution medium is 0.05 M sodiumphosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first layer, and wherein Compound 1, Compound 2 andCompound 3 are formulated in the same amorphous solid dispersion whichcomprises copovidone, vitamin E TPGS, lauroglycol and sorbitanmonolaurate. The amorphous solid dispersion can be milled and compressedinto the first layer. The second layer comprises 216.2 mg Compound 4monosodium salt monohydrate, 30% copovidone, and 30% hypromellose,wherein all percentages are weight percentages relative to the totalweight of the second layer. When the pharmaceutical solid dosage form isdissolved in 900 mL of a dissolution medium using a standard USPdissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., thesolid dosage form can have the following release profile: 100% Compound1 in the solid dosage form is released within 8 hours, 100% Compound 2in the solid dosage form is released within 8 hours, 100% Compound 3 inthe solid dosage form is released within 8 hours, 20-30% Compound 4 inthe solid dosage form is released within 8 hours, 30-40% Compound 4 inthe solid dosage form is released within 12 hours, 40-60% Compound 4 inthe solid dosage form is released within 16 hours, and 60-80% Compound 4in the solid dosage form is released within 24 hours. The dissolutionmedium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as asurfactant.

In another embodiment, the present invention features a pharmaceuticalsolid dosage form which is a tablet comprising two layers. The firstlayer comprises Compound 1, Compound 2 and Compound 3, each of which isformulated in amorphous solid dispersion, and the second layer comprisesa pharmaceutically acceptable salt of Compound 4 in a crystalline form.The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8%Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer ora combination of pharmaceutically acceptable hydrophilic polymers, and5-10% a pharmaceutically acceptable surfactant or a combination ofpharmaceutically acceptable surfactants, wherein all percentages areweight percentages relative to the total weight of the first layer, andwherein Compound 1, Compound 2 and Compound 3 are each formulated inseparate amorphous solid dispersions, and each solid dispersioncomprises (1) the hydrophilic polymer or the combination of hydrophilicpolymers and (2) the surfactant or one of the combination ofsurfactants. These amorphous solid dispersions can be milled and thencompressed into the first layer. The second layer comprises 30-50% apharmaceutically acceptable salt of Compound 4, 20-40% apharmaceutically acceptable stabilizing polymer or a combination ofpharmaceutically acceptable stabilizing polymers, and 20-40% apharmaceutically acceptable release rate-modifying polymer or acombination of pharmaceutically acceptable release rate-modifyingpolymers, wherein all percentages are weight percentages relative to thetotal weight of the second layer. When the pharmaceutical solid dosageform is dissolved in 900 mL of a dissolution medium using a standard USPdissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., thesolid dosage form can have the following release profile: 100% Compound1 in the solid dosage form is released within 8 hours, 100% Compound 2in the solid dosage form is released within 8 hours, 100% Compound 3 inthe solid dosage form is released within 8 hours, 20-30% Compound 4 inthe solid dosage form is released within 8 hours, 30-40% Compound 4 inthe solid dosage form is released within 12 hours, 40-60% Compound 4 inthe solid dosage form is released within 16 hours, and 60-80% Compound 4in the solid dosage form is released within 24 hours. The dissolutionmedium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as asurfactant.

In another embodiment, the present invention features a pharmaceuticalsolid dosage form which is a tablet comprising two layers. The firstlayer comprises Compound 1, Compound 2 and Compound 3, each of which isformulated in amorphous solid dispersion, and the second layer comprisesa pharmaceutically acceptable salt of Compound 4 in a crystalline form.The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mgCompound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer ora combination of pharmaceutically acceptable hydrophilic polymers, and5-10% a pharmaceutically acceptable surfactant or a combination ofpharmaceutically acceptable surfactants, wherein all percentages areweight percentages relative to the total weight of the first layer, andwherein Compound 1, Compound 2 and Compound 3 are each formulated inseparate amorphous solid dispersions, and each solid dispersioncomprises (1) the hydrophilic polymer or one of the combination ofhydrophilic polymers and (2) the surfactant or one of the combination ofsurfactants. These amorphous solid dispersions can be milled and thencompressed into the first layer. The second layer comprises apharmaceutically acceptable salt of Compound 4 in an amount equivalentto 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium saltmonohydrate), 20-40% a pharmaceutically acceptable stabilizing polymeror a combination of pharmaceutically acceptable stabilizing polymers,and 20-40% a pharmaceutically acceptable release rate-modifying polymeror a combination of pharmaceutically acceptable release rate-modifyingpolymers, wherein all percentages are weight percentages relative to thetotal weight of the second layer. When the pharmaceutical solid dosageform is dissolved in 900 mL of a dissolution medium using a standard USPdissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., thesolid dosage form can have the following release profile: 100% Compound1 in the solid dosage form is released within 8 hours, 100% Compound 2in the solid dosage form is released within 8 hours, 100% Compound 3 inthe solid dosage form is released within 8 hours, 20-30% Compound 4 inthe solid dosage form is released within 8 hours, 30-40% Compound 4 inthe solid dosage form is released within 12 hours, 40-60% Compound 4 inthe solid dosage form is released within 16 hours, and 60-80% Compound 4in the solid dosage form is released within 24 hours. The dissolutionmedium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as asurfactant.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptablehydrophilic polymer or a combination of pharmaceutically acceptablehydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactantor a combination of pharmaceutically acceptable surfactants, wherein allpercentages are weight percentages relative to the total weight of thefirst layer, and wherein Compound 1, Compound 2 and Compound 3 are eachformulated in separate amorphous solid dispersions, and each soliddispersion comprises (1) the hydrophilic polymer or one of thecombination of hydrophilic polymers and (2) the surfactant or one of thecombination of surfactants. These amorphous solid dispersions can bemilled and then compressed into the first layer. The second layercomprises 216.2 mg Compound 4 monosodium salt monohydrate, 20-40% apharmaceutically acceptable stabilizing polymer or a combination ofpharmaceutically acceptable stabilizing polymers, and 20-40% apharmaceutically acceptable release rate-modifying polymer or acombination of pharmaceutically acceptable release rate-modifyingpolymers, wherein all percentages are weight percentages relative to thetotal weight of the second layer. When the pharmaceutical solid dosageform is dissolved in 900 mL of a dissolution medium using a standard USPdissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., thesolid dosage form can have the following release profile: 100% Compound1 in the solid dosage form is released within 8 hours, 100% Compound 2in the solid dosage form is released within 8 hours, 100% Compound 3 inthe solid dosage form is released within 8 hours, 20-30% Compound 4 inthe solid dosage form is released within 8 hours, 30-40% Compound 4 inthe solid dosage form is released within 12 hours, 40-60% Compound 4 inthe solid dosage form is released within 16 hours, and 60-80% Compound 4in the solid dosage form is released within 24 hours. The dissolutionmedium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as asurfactant.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5%Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combinationof vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein allpercentages are weight percentages relative to the total weight of thefirst layer, and wherein Compound 1, Compound 2 and Compound 3 are eachformulated in separate amorphous solid dispersions. The solid dispersioncomprising Compound 1 can comprise copovidone, vitamin E TPGS andlauroglycol; the solid dispersion comprising Compound 2 can comprisecopovidone and vitamin E TPGS; and the solid dispersion comprisingCompound 3 can comprise copovidone and sorbitan monolaurate. Theseamorphous solid dispersions can be milled and then compressed into thefirst layer. The second layer comprises 30-50% a pharmaceuticallyacceptable salt of Compound 4, 20-40% copovidone, and 20-40%hypromellose, wherein all percentages are weight percentages relative tothe total weight of the second layer. When the pharmaceutical soliddosage form is dissolved in 900 mL of a dissolution medium using astandard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at37° C., the solid dosage form can have the following release profile:100% Compound 1 in the solid dosage form is released within 8 hours,100% Compound 2 in the solid dosage form is released within 8 hours,100% Compound 3 in the solid dosage form is released within 8 hours,20-30% Compound 4 in the solid dosage form is released within 8 hours,30-40% Compound 4 in the solid dosage form is released within 12 hours,40-60% Compound 4 in the solid dosage form is released within 16 hours,and 60-80% Compound 4 in the solid dosage form is released within 24hours. The dissolution medium is 0.05 M sodium phosphate buffer (pH 6.8)with 15 mM cTAB as a surfactant.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first layer, and wherein Compound 1, Compound 2 andCompound 3 are each formulated in separate amorphous solid dispersions.The solid dispersion comprising Compound 1 can comprise copovidone,vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound2 can comprise copovidone and vitamin E TPGS; and the solid dispersioncomprising Compound 3 can comprise copovidone and sorbitan monolaurate.These amorphous solid dispersions can be milled and then compressed intothe first layer. The second layer comprises a pharmaceuticallyacceptable salt of Compound 4 in an amount equivalent to 200 mg Compound4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40%copovidone, and 20-40% hypromellose, wherein all percentages are weightpercentages relative to the total weight of the second layer. When thepharmaceutical solid dosage form is dissolved in 900 mL of a dissolutionmedium using a standard USP dissolution Apparatus 2 (paddle) operatingat 100 RPM at 37° C., the solid dosage form can have the followingrelease profile: 100% Compound 1 in the solid dosage form is releasedwithin 8 hours, 100% Compound 2 in the solid dosage form is releasedwithin 8 hours, 100% Compound 3 in the solid dosage form is releasedwithin 8 hours, 20-30% Compound 4 in the solid dosage form is releasedwithin 8 hours, 30-40% Compound 4 in the solid dosage form is releasedwithin 12 hours, 40-60% Compound 4 in the solid dosage form is releasedwithin 16 hours, and 60-80% Compound 4 in the solid dosage form isreleased within 24 hours. The dissolution medium is 0.05 M sodiumphosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first layer, and wherein Compound 1, Compound 2 andCompound 3 are each formulated in separate amorphous solid dispersions.The solid dispersion comprising Compound 1 can comprise copovidone,vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound2 can comprise copovidone and vitamin E TPGS; and the solid dispersioncomprising Compound 3 can comprise copovidone and sorbitan monolaurate.These amorphous solid dispersions can be milled and then compressed intothe first layer. The second layer comprises 216.2 mg Compound 4monosodium salt monohydrate, 20-40% copovidone, and 20-40% hypromellose,wherein all percentages are weight percentages relative to the totalweight of the second layer. When the pharmaceutical solid dosage form isdissolved in 900 mL of a dissolution medium using a standard USPdissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., thesolid dosage form can have the following release profile: 100% Compound1 in the solid dosage form is released within 8 hours, 100% Compound 2in the solid dosage form is released within 8 hours, 100% Compound 3 inthe solid dosage form is released within 8 hours, 20-30% Compound 4 inthe solid dosage form is released within 8 hours, 30-40% Compound 4 inthe solid dosage form is released within 12 hours, 40-60% Compound 4 inthe solid dosage form is released within 16 hours, and 60-80% Compound 4in the solid dosage form is released within 24 hours. The dissolutionmedium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as asurfactant.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5%Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combinationof vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein allpercentages are weight percentages relative to the total weight of thefirst layer, and wherein Compound 1, Compound 2 and Compound 3 are eachformulated in separate amorphous solid dispersions. The solid dispersioncomprising Compound 1 can comprise copovidone, vitamin E TPGS andlauroglycol; the solid dispersion comprising Compound 2 can comprisecopovidone and vitamin E TPGS; and the solid dispersion comprisingCompound 3 can comprise copovidone and sorbitan monolaurate. Theseamorphous solid dispersions can be milled and then compressed into thefirst layer. The second layer comprises 30-50% a pharmaceuticallyacceptable salt of Compound 4, 30% copovidone, and 30% hypromellose,wherein all percentages are weight percentages relative to the totalweight of the second layer. When the pharmaceutical solid dosage form isdissolved in 900 mL of a dissolution medium using a standard USPdissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., thesolid dosage form can have the following release profile: 100% Compound1 in the solid dosage form is released within 8 hours, 100% Compound 2in the solid dosage form is released within 8 hours, 100% Compound 3 inthe solid dosage form is released within 8 hours, 20-30% Compound 4 inthe solid dosage form is released within 8 hours, 30-40% Compound 4 inthe solid dosage form is released within 12 hours, 40-60% Compound 4 inthe solid dosage form is released within 16 hours, and 60-80% Compound 4in the solid dosage form is released within 24 hours. The dissolutionmedium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as asurfactant.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first layer, and wherein Compound 1, Compound 2 andCompound 3 are each formulated in separate amorphous solid dispersions.The solid dispersion comprising Compound 1 can comprise copovidone,vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound2 can comprise copovidone and vitamin E TPGS; and the solid dispersioncomprising Compound 3 can comprise copovidone and sorbitan monolaurate.These amorphous solid dispersions can be milled and then compressed intothe first layer. The second layer comprises a pharmaceuticallyacceptable salt of Compound 4 in an amount equivalent to 200 mg Compound4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 30%copovidone, and 30% hypromellose, wherein all percentages are weightpercentages relative to the total weight of the second layer. When thepharmaceutical solid dosage form is dissolved in 900 mL of a dissolutionmedium using a standard USP dissolution Apparatus 2 (paddle) operatingat 100 RPM at 37° C., the solid dosage form can have the followingrelease profile: 100% Compound 1 in the solid dosage form is releasedwithin 8 hours, 100% Compound 2 in the solid dosage form is releasedwithin 8 hours, 100% Compound 3 in the solid dosage form is releasedwithin 8 hours, 20-30% Compound 4 in the solid dosage form is releasedwithin 8 hours, 30-40% Compound 4 in the solid dosage form is releasedwithin 12 hours, 40-60% Compound 4 in the solid dosage form is releasedwithin 16 hours, and 60-80% Compound 4 in the solid dosage form isreleased within 24 hours. The dissolution medium is 0.05 M sodiumphosphate buffer (pH 6.8) with 15 mM cTAB as a surfactant.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first layer, and wherein Compound 1, Compound 2 andCompound 3 are each formulated in separate amorphous solid dispersions.The solid dispersion comprising Compound 1 can comprise copovidone,vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound2 can comprise copovidone and vitamin E TPGS; and the solid dispersioncomprising Compound 3 can comprise copovidone and sorbitan monolaurate.These amorphous solid dispersions can be milled and then compressed intothe first layer. The second layer comprises 216.2 mg Compound 4monosodium salt monohydrate, 30% copovidone, and 30% hypromellose,wherein all percentages are weight percentages relative to the totalweight of the second layer. When the pharmaceutical solid dosage form isdissolved in 900 mL of a dissolution medium using a standard USPdissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., thesolid dosage form can have the following release profile: 100% Compound1 in the solid dosage form is released within 8 hours, 100% Compound 2in the solid dosage form is released within 8 hours, 100% Compound 3 inthe solid dosage form is released within 8 hours, 20-30% Compound 4 inthe solid dosage form is released within 8 hours, 30-40% Compound 4 inthe solid dosage form is released within 12 hours, 40-60% Compound 4 inthe solid dosage form is released within 16 hours, and 60-80% Compound 4in the solid dosage form is released within 24 hours. The dissolutionmedium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB as asurfactant.

In each and every embodiment, aspect and example described in thisdisclosure, when a single dose consisting of the same three solid dosageforms is administered to humans under non-fasting conditions, it can,for example, produce the following pharmacokinetics profile: the AUC_(∞)for Compound 1 is 4000-5000 ng·h/mL, the AUC_(∞) for Compound 2 is1500-2500 ng·h/mL, the AUC_(∞) for Compound 3 is 7000-9000 ng·h/mL, andthe AUC_(∞) for Compound 4 is 10000-20000 ng·h/mL.

Accordingly, in another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5%Compound 2, 2-8% Compound 3, 70-85% a pharmaceutically acceptablehydrophilic polymer or a combination of pharmaceutically acceptablehydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactantor a combination of pharmaceutically acceptable surfactants, wherein allpercentages are weight percentages relative to the total weight of thefirst layer. The second layer comprises 30-50% a pharmaceuticallyacceptable salt of Compound 4, 20-40% a pharmaceutically acceptablestabilizing polymer or a combination of pharmaceutically acceptablestabilizing polymers, and 20-40% a pharmaceutically acceptable releaserate-modifying polymer or a combination of pharmaceutically acceptablerelease rate-modifying polymers, wherein all percentages are weightpercentages relative to the total weight of the second layer. When asingle dose consisting of three solid dosage forms of this embodiment isadministered to humans under non-fasting conditions, the AUC_(∞) forCompound 1 is 4000-5000 ng·h/mL, the AUC_(∞) for Compound 2 is 1500-2500ng·h/mL, the AUC_(∞) for Compound 3 is 7000-9000 ng·h/mL, and theAUC_(∞) for Compound 4 is 10000-20000 ng·h/mL.

In another embodiment, the present invention features a pharmaceuticalsolid dosage form which is a tablet comprising two layers. The firstlayer comprises Compound 1, Compound 2 and Compound 3, each of which isformulated in amorphous solid dispersion, and the second layer comprisesa pharmaceutically acceptable salt of Compound 4 in a crystalline form.The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mgCompound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer ora combination of pharmaceutically acceptable hydrophilic polymers, and5-10% a pharmaceutically acceptable surfactant or a combination ofpharmaceutically acceptable surfactants, wherein all percentages areweight percentages relative to the total weight of the first layer. Thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in an amount equivalent to 200 mg Compound 4 (e.g., 216.2 mg Compound 4monosodium salt monohydrate), 20-40% a pharmaceutically acceptablestabilizing polymer or a combination of pharmaceutically acceptablestabilizing polymers, and 20-40% a pharmaceutically acceptable releaserate-modifying polymer or a combination of pharmaceutically acceptablerelease rate-modifying polymers, wherein all percentages are weightpercentages relative to the total weight of the second layer. When asingle dose consisting of three solid dosage forms of this embodiment isadministered to humans under non-fasting conditions, the AUC∞ forCompound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ forCompound 4 is 10000-20000 ng·h/mL.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptablehydrophilic polymer or a combination of pharmaceutically acceptablehydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactantor a combination of pharmaceutically acceptable surfactants, wherein allpercentages are weight percentages relative to the total weight of thefirst layer. The second layer comprises 216.2 mg Compound 4 monosodiumsalt monohydrate, 20-40% a pharmaceutically acceptable stabilizingpolymer or a combination of pharmaceutically acceptable stabilizingpolymers, and 20-40% a pharmaceutically acceptable releaserate-modifying polymer or a combination of pharmaceutically acceptablerelease rate-modifying polymers, wherein all percentages are weightpercentages relative to the total weight of the second layer. When asingle dose consisting of three solid dosage forms of this embodiment isadministered to humans under non-fasting conditions, the AUC∞ forCompound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ forCompound 4 is 10000-20000 ng·h/mL.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5%Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combinationof vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein allpercentages are weight percentages relative to the total weight of thefirst layer. The second layer comprises 30-50% a pharmaceuticallyacceptable salt of Compound 4, 20-40% copovidone, and 20-40%hypromellose, wherein all percentages are weight percentages relative tothe total weight of the second layer. When a single dose consisting ofthree solid dosage forms of this embodiment is administered to humansunder non-fasting conditions, the AUC∞ for Compound 1 is 4000-5000ng·h/mL, the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ forCompound 3 is 7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is10000-20000 ng·h/mL.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, sorbitan monolaurate and lauroglycol,wherein all percentages are weight percentages relative to the totalweight of the first layer. The second layer comprises a pharmaceuticallyacceptable salt of Compound 4 in an amount equivalent to 200 mg Compound4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40%copovidone, and 20-40% hypromellose, wherein all percentages are weightpercentages relative to the total weight of the second layer. When asingle dose consisting of three solid dosage forms of this embodiment isadministered to humans under non-fasting conditions, the AUC∞ forCompound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ forCompound 4 is 10000-20000 ng·h/mL.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, sorbitan monolaurate and lauroglycol,wherein all percentages are weight percentages relative to the totalweight of the first layer. The second layer comprises 216.2 mg Compound4 monosodium salt monohydrate, 20-40% copovidone, and 20-40%hypromellose, wherein all percentages are weight percentages relative tothe total weight of the second layer. When a single dose consisting ofthree solid dosage forms of this embodiment is administered to humansunder non-fasting conditions, the AUC∞ for Compound 1 is 4000-5000ng·h/mL, the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ forCompound 3 is 7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is10000-20000 ng·h/mL.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5%Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combinationof vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein allpercentages are weight percentages relative to the total weight of thefirst layer. The second layer comprises 30-50% a pharmaceuticallyacceptable salt of Compound 4, 30% copovidone, and 30% hypromellose,wherein all percentages are weight percentages relative to the totalweight of the second layer. When a single dose consisting of three soliddosage forms of this embodiment is administered to humans undernon-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL,the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, sorbitan monolaurate and lauroglycol,wherein all percentages are weight percentages relative to the totalweight of the first layer. The second layer comprises a pharmaceuticallyacceptable salt of Compound 4 in an amount equivalent to 200 mg Compound4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 30%copovidone, and 30% hypromellose, wherein all percentages are weightpercentages relative to the total weight of the second layer. When asingle dose consisting of three solid dosage forms of this embodiment isadministered to humans under non-fasting conditions, the AUC∞ forCompound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ forCompound 4 is 10000-20000 ng·h/mL.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, sorbitan monolaurate and lauroglycol,wherein all percentages are weight percentages relative to the totalweight of the first layer. The second layer comprises 216.2 mg Compound4 monosodium salt monohydrate, 30% copovidone, and 30% hypromellose,wherein all percentages are weight percentages relative to the totalweight of the second layer. When a single dose consisting of three soliddosage forms of this embodiment is administered to humans undernon-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL,the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.

In another embodiment, the present invention features a pharmaceuticalsolid dosage form which is a tablet comprising two layers. The firstlayer comprises Compound 1, Compound 2 and Compound 3, each of which isformulated in amorphous solid dispersion, and the second layer comprisesa pharmaceutically acceptable salt of Compound 4 in a crystalline form.The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8%Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer ora combination of pharmaceutically acceptable hydrophilic polymers, and5-10% a pharmaceutically acceptable surfactant or a combination ofpharmaceutically acceptable surfactants, wherein all percentages areweight percentages relative to the total weight of the first layer, andwherein Compound 1, Compound 2 and Compound 3 are formulated in the sameamorphous solid dispersion which comprises (1) the hydrophilic polymeror the combination of hydrophilic polymers and (2) the surfactant or thecombination of surfactants. The amorphous solid dispersion can be milledand compressed into the first layer. The second layer comprises 30-50% apharmaceutically acceptable salt of Compound 4, 20-40% apharmaceutically acceptable stabilizing polymer or a combination ofpharmaceutically acceptable stabilizing polymers, and 20-40% apharmaceutically acceptable release rate-modifying polymer or acombination of pharmaceutically acceptable release rate-modifyingpolymers, wherein all percentages are weight percentages relative to thetotal weight of the second layer. When a single dose consisting of threesolid dosage forms of this embodiment is administered to humans undernon-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL,the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.

In another embodiment, the present invention features a pharmaceuticalsolid dosage form which is a tablet comprising two layers. The firstlayer comprises Compound 1, Compound 2 and Compound 3, each of which isformulated in amorphous solid dispersion, and the second layer comprisesa pharmaceutically acceptable salt of Compound 4 in a crystalline form.The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mgCompound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer ora combination of pharmaceutically acceptable hydrophilic polymers, and5-10% a pharmaceutically acceptable surfactant or a combination ofpharmaceutically acceptable surfactants, wherein all percentages areweight percentages relative to the total weight of the first layer, andwherein Compound 1, Compound 2 and Compound 3 are formulated in the sameamorphous solid dispersion which comprises (1) the hydrophilic polymeror the combination of hydrophilic polymers and (2) the surfactant or thecombination of surfactants. The amorphous solid dispersion can be milledand compressed into the first layer. The second layer comprises apharmaceutically acceptable salt of Compound 4 in an amount equivalentto 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium saltmonohydrate), 20-40% a pharmaceutically acceptable stabilizing polymeror a combination of pharmaceutically acceptable stabilizing polymers,and 20-40% a pharmaceutically acceptable release rate-modifying polymeror a combination of pharmaceutically acceptable release rate-modifyingpolymers, wherein all percentages are weight percentages relative to thetotal weight of the second layer. When a single dose consisting of threesolid dosage forms of this embodiment is administered to humans undernon-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL,the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptablehydrophilic polymer or a combination of pharmaceutically acceptablehydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactantor a combination of pharmaceutically acceptable surfactants, wherein allpercentages are weight percentages relative to the total weight of thefirst layer, and wherein Compound 1, Compound 2 and Compound 3 areformulated in the same amorphous solid dispersion which comprises (1)the hydrophilic polymer or the combination of hydrophilic polymers and(2) the surfactant or the combination of surfactants. The amorphoussolid dispersion can be milled and compressed into the first layer. Thesecond layer comprises 216.2 mg Compound 4 monosodium salt monohydrate,20-40% a pharmaceutically acceptable stabilizing polymer or acombination of pharmaceutically acceptable stabilizing polymers, and20-40% a pharmaceutically acceptable release rate-modifying polymer or acombination of pharmaceutically acceptable release rate-modifyingpolymers, wherein all percentages are weight percentages relative to thetotal weight of the second layer. When a single dose consisting of threesolid dosage forms of this embodiment is administered to humans undernon-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL,the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5%Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combinationof vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein allpercentages are weight percentages relative to the total weight of thefirst layer, and wherein Compound 1, Compound 2 and Compound 3 areformulated in the same amorphous solid dispersion which comprisescopovidone, vitamin E TPGS, lauroglycol and sorbitan monolaurate. Theamorphous solid dispersion can be milled and compressed into the firstlayer. The second layer comprises 30-50% a pharmaceutically acceptablesalt of Compound 4, 20-40% copovidone, and 20-40% hypromellose, whereinall percentages are weight percentages relative to the total weight ofthe second layer. When a single dose consisting of three solid dosageforms of this embodiment is administered to humans under non-fastingconditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL, the AUC∞ forCompound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is 7000-9000ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first layer, and wherein Compound 1, Compound 2 andCompound 3 are formulated in the same amorphous solid dispersion whichcomprises copovidone, vitamin E TPGS, lauroglycol and sorbitanmonolaurate. The amorphous solid dispersion can be milled and compressedinto the first layer. The second layer comprises a pharmaceuticallyacceptable salt of Compound 4 in an amount equivalent to 200 mg Compound4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40%copovidone, and 20-40% hypromellose, wherein all percentages are weightpercentages relative to the total weight of the second layer. When asingle dose consisting of three solid dosage forms of this embodiment isadministered to humans under non-fasting conditions, the AUC∞ forCompound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ forCompound 4 is 10000-20000 ng·h/mL.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first layer, and wherein Compound 1, Compound 2 andCompound 3 are formulated in the same amorphous solid dispersion whichcomprises copovidone, vitamin E TPGS, lauroglycol and sorbitanmonolaurate. The amorphous solid dispersion can be milled and compressedinto the first layer. The second layer comprises 216.2 mg Compound 4monosodium salt monohydrate, 20-40% copovidone, and 20-40% hypromellose,wherein all percentages are weight percentages relative to the totalweight of the second layer. When a single dose consisting of three soliddosage forms of this embodiment is administered to humans undernon-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL,the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5%Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combinationof vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein allpercentages are weight percentages relative to the total weight of thefirst layer, and wherein Compound 1, Compound 2 and Compound 3 areformulated in the same amorphous solid dispersion which comprisescopovidone, vitamin E TPGS, lauroglycol and sorbitan monolaurate. Theamorphous solid dispersion can be milled and compressed into the firstlayer. The second layer comprises 30-50% a pharmaceutically acceptablesalt of Compound 4, 30% copovidone, and 30% hypromellose, wherein allpercentages are weight percentages relative to the total weight of thesecond layer. When a single dose consisting of three solid dosage formsof this embodiment is administered to humans under non-fastingconditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL, the AUC∞ forCompound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is 7000-9000ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first layer, and wherein Compound 1, Compound 2 andCompound 3 are formulated in the same amorphous solid dispersion whichcomprises copovidone, vitamin E TPGS, lauroglycol and sorbitanmonolaurate. The amorphous solid dispersion can be milled and compressedinto the first layer. The second layer comprises a pharmaceuticallyacceptable salt of Compound 4 in an amount equivalent to 200 mg Compound4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 30%copovidone, and 30% hypromellose, wherein all percentages are weightpercentages relative to the total weight of the second layer. When asingle dose consisting of three solid dosage forms of this embodiment isadministered to humans under non-fasting conditions, the AUC∞ forCompound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ forCompound 4 is 10000-20000 ng·h/mL.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first layer, and wherein Compound 1, Compound 2 andCompound 3 are formulated in the same amorphous solid dispersion whichcomprises copovidone, vitamin E TPGS, lauroglycol and sorbitanmonolaurate. The amorphous solid dispersion can be milled and compressedinto the first layer. The second layer comprises 216.2 mg Compound 4monosodium salt monohydrate, 30% copovidone, and 30% hypromellose,wherein all percentages are weight percentages relative to the totalweight of the second layer. When a single dose consisting of three soliddosage forms of this embodiment is administered to humans undernon-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL,the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.

In another embodiment, the present invention features a pharmaceuticalsolid dosage form which is a tablet comprising two layers. The firstlayer comprises Compound 1, Compound 2 and Compound 3, each of which isformulated in amorphous solid dispersion, and the second layer comprisesa pharmaceutically acceptable salt of Compound 4 in a crystalline form.The first layer comprises 5-10% Compound 1, 1-5% Compound 2, 2-8%Compound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer ora combination of pharmaceutically acceptable hydrophilic polymers, and5-10% a pharmaceutically acceptable surfactant or a combination ofpharmaceutically acceptable surfactants, wherein all percentages areweight percentages relative to the total weight of the first layer, andwherein Compound 1, Compound 2 and Compound 3 are each formulated inseparate amorphous solid dispersions, and each solid dispersioncomprises (1) the hydrophilic polymer or the combination of hydrophilicpolymers and (2) the surfactant or one of the combination ofsurfactants. These amorphous solid dispersions can be milled and thencompressed into the first layer. The second layer comprises 30-50% apharmaceutically acceptable salt of Compound 4, 20-40% apharmaceutically acceptable stabilizing polymer or a combination ofpharmaceutically acceptable stabilizing polymers, and 20-40% apharmaceutically acceptable release rate-modifying polymer or acombination of pharmaceutically acceptable release rate-modifyingpolymers, wherein all percentages are weight percentages relative to thetotal weight of the second layer. When a single dose consisting of threesolid dosage forms of this embodiment is administered to humans undernon-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL,the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.

In another embodiment, the present invention features a pharmaceuticalsolid dosage form which is a tablet comprising two layers. The firstlayer comprises Compound 1, Compound 2 and Compound 3, each of which isformulated in amorphous solid dispersion, and the second layer comprisesa pharmaceutically acceptable salt of Compound 4 in a crystalline form.The first layer comprises 50 mg Compound 1, 8.33 mg Compound 2, 33.33 mgCompound 3, 70-85% a pharmaceutically acceptable hydrophilic polymer ora combination of pharmaceutically acceptable hydrophilic polymers, and5-10% a pharmaceutically acceptable surfactant or a combination ofpharmaceutically acceptable surfactants, wherein all percentages areweight percentages relative to the total weight of the first layer, andwherein Compound 1, Compound 2 and Compound 3 are each formulated inseparate amorphous solid dispersions, and each solid dispersioncomprises (1) the hydrophilic polymer or one of the combination ofhydrophilic polymers and (2) the surfactant or one of the combination ofsurfactants. These amorphous solid dispersions can be milled and thencompressed into the first layer. The second layer comprises apharmaceutically acceptable salt of Compound 4 in an amount equivalentto 200 mg Compound 4 (e.g., 216.2 mg Compound 4 monosodium saltmonohydrate), 20-40% a pharmaceutically acceptable stabilizing polymeror a combination of pharmaceutically acceptable stabilizing polymers,and 20-40% a pharmaceutically acceptable release rate-modifying polymeror a combination of pharmaceutically acceptable release rate-modifyingpolymers, wherein all percentages are weight percentages relative to thetotal weight of the second layer. When a single dose consisting of threesolid dosage forms of this embodiment is administered to humans undernon-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL,the AUC_(∞) for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3is 7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000ng·h/mL.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% a pharmaceutically acceptablehydrophilic polymer or a combination of pharmaceutically acceptablehydrophilic polymers, and 5-10% a pharmaceutically acceptable surfactantor a combination of pharmaceutically acceptable surfactants, wherein allpercentages are weight percentages relative to the total weight of thefirst layer, and wherein Compound 1, Compound 2 and Compound 3 are eachformulated in separate amorphous solid dispersions, and each soliddispersion comprises (1) the hydrophilic polymer or one of thecombination of hydrophilic polymers and (2) the surfactant or one of thecombination of surfactants. These amorphous solid dispersions can bemilled and then compressed into the first layer. The second layercomprises 216.2 mg Compound 4 monosodium salt monohydrate, 20-40% apharmaceutically acceptable stabilizing polymer or a combination ofpharmaceutically acceptable stabilizing polymers, and 20-40% apharmaceutically acceptable release rate-modifying polymer or acombination of pharmaceutically acceptable release rate-modifyingpolymers, wherein all percentages are weight percentages relative to thetotal weight of the second layer. When a single dose consisting of threesolid dosage forms of this embodiment is administered to humans undernon-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL,the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5%Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combinationof vitamin E TPGS, sorbitan monolaurate and lauroglycol, wherein allpercentages are weight percentages relative to the total weight of thefirst layer, and wherein Compound 1, Compound 2 and Compound 3 are eachformulated in separate amorphous solid dispersions. The solid dispersioncomprising Compound 1 can comprise copovidone, vitamin E TPGS andlauroglycol; the solid dispersion comprising Compound 2 can comprisecopovidone and vitamin E TPGS; and the solid dispersion comprisingCompound 3 can comprise copovidone and sorbitan monolaurate. Theseamorphous solid dispersions can be milled and then compressed into thefirst layer. The second layer comprises 30-50% a pharmaceuticallyacceptable salt of Compound 4, 20-40% copovidone, and 20-40%hypromellose, wherein all percentages are weight percentages relative tothe total weight of the second layer. When a single dose consisting ofthree solid dosage forms of this embodiment is administered to humansunder non-fasting conditions, the AUC∞ for Compound 1 is 4000-5000ng·h/mL, the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ forCompound 3 is 7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is10000-20000 ng·h/mL.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first layer, and wherein Compound 1, Compound 2 andCompound 3 are each formulated in separate amorphous solid dispersions.The solid dispersion comprising Compound 1 can comprise copovidone,vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound2 can comprise copovidone and vitamin E TPGS; and the solid dispersioncomprising Compound 3 can comprise copovidone and sorbitan monolaurate.These amorphous solid dispersions can be milled and then compressed intothe first layer. The second layer comprises a pharmaceuticallyacceptable salt of Compound 4 in an amount equivalent to 200 mg Compound4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 20-40%copovidone, and 20-40% hypromellose, wherein all percentages are weightpercentages relative to the total weight of the second layer. When asingle dose consisting of three solid dosage forms of this embodiment isadministered to humans under non-fasting conditions, the AUC∞ forCompound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ forCompound 4 is 10000-20000 ng·h/mL.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first layer, and wherein Compound 1, Compound 2 andCompound 3 are each formulated in separate amorphous solid dispersions.The solid dispersion comprising Compound 1 can comprise copovidone,vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound2 can comprise copovidone and vitamin E TPGS; and the solid dispersioncomprising Compound 3 can comprise copovidone and sorbitan monolaurate.These amorphous solid dispersions can be milled and then compressed intothe first layer. The second layer comprises 216.2 mg Compound 4monosodium salt monohydrate, 20-40% copovidone, and 20-40% hypromellose,wherein all percentages are weight percentages relative to the totalweight of the second layer. When a single dose consisting of three soliddosage forms of this embodiment is administered to humans undernon-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL,the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 5-10% Compound 1, 1-5%Compound 2, 2-8% Compound 3, 70-85% copovidone, and 5-10% a combinationof vitamin E TPGS, lauroglycol and sorbitan monolaurate, wherein allpercentages are weight percentages relative to the total weight of thefirst layer, and wherein Compound 1, Compound 2 and Compound 3 are eachformulated in separate amorphous solid dispersions. The solid dispersioncomprising Compound 1 can comprise copovidone, vitamin E TPGS andlauroglycol; the solid dispersion comprising Compound 2 can comprisecopovidone and vitamin E TPGS; and the solid dispersion comprisingCompound 3 can comprise copovidone and sorbitan monolaurate. Theseamorphous solid dispersions can be milled and then compressed into thefirst layer. The second layer comprises 30-50% a pharmaceuticallyacceptable salt of Compound 4, 30% copovidone, and 30% hypromellose,wherein all percentages are weight percentages relative to the totalweight of the second layer. When a single dose consisting of three soliddosage forms of this embodiment is administered to humans undernon-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL,the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first layer, and wherein Compound 1, Compound 2 andCompound 3 are each formulated in separate amorphous solid dispersions.The solid dispersion comprising Compound 1 can comprise copovidone,vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound2 can comprise copovidone and vitamin E TPGS; and the solid dispersioncomprising Compound 3 can comprise copovidone and sorbitan monolaurate.These amorphous solid dispersions can be milled and then compressed intothe first layer. The second layer comprises a pharmaceuticallyacceptable salt of Compound 4 in an amount equivalent to 200 mg Compound4 (e.g., 216.2 mg Compound 4 monosodium salt monohydrate), 30%copovidone, and 30% hypromellose, wherein all percentages are weightpercentages relative to the total weight of the second layer. When asingle dose consisting of three solid dosage forms of this embodiment isadministered to humans under non-fasting conditions, the AUC∞ forCompound 1 is 4000-5000 ng·h/mL, the AUC∞ for Compound 2 is 1500-2500ng·h/mL, the AUC∞ for Compound 3 is 7000-9000 ng·h/mL, and the AUC∞ forCompound 4 is 10000-20000 ng·h/mL.

In yet another embodiment, the present invention features apharmaceutical solid dosage form which is a tablet comprising twolayers. The first layer comprises Compound 1, Compound 2 and Compound 3,each of which is formulated in amorphous solid dispersion, and thesecond layer comprises a pharmaceutically acceptable salt of Compound 4in a crystalline form. The first layer comprises 50 mg Compound 1, 8.33mg Compound 2, 33.33 mg Compound 3, 70-85% copovidone, and 5-10% acombination of vitamin E TPGS, lauroglycol and sorbitan monolaurate,wherein all percentages are weight percentages relative to the totalweight of the first layer, and wherein Compound 1, Compound 2 andCompound 3 are each formulated in separate amorphous solid dispersions.The solid dispersion comprising Compound 1 can comprise copovidone,vitamin E TPGS and lauroglycol; the solid dispersion comprising Compound2 can comprise copovidone and vitamin E TPGS; and the solid dispersioncomprising Compound 3 can comprise copovidone and sorbitan monolaurate.These amorphous solid dispersions can be milled and then compressed intothe first layer. The second layer comprises 216.2 mg Compound 4monosodium salt monohydrate, 30% copovidone, and 30% hypromellose,wherein all percentages are weight percentages relative to the totalweight of the second layer. When a single dose consisting of three soliddosage forms of this embodiment is administered to humans undernon-fasting conditions, the AUC∞ for Compound 1 is 4000-5000 ng·h/mL,the AUC∞ for Compound 2 is 1500-2500 ng·h/mL, the AUC∞ for Compound 3 is7000-9000 ng·h/mL, and the AUC∞ for Compound 4 is 10000-20000 ng·h/mL.

In each and every embodiment, aspect and example described in thisapplication, the size of the pharmaceutical solid dosage form can be,for example, 1000-1600 mg.

In each and every embodiment, aspect and example described in thisdisclosure, the size of the pharmaceutical solid dosage form can be, forexample, 1200-1400 mg.

In each and every embodiment, aspect and example described in thisdisclosure, the size of the pharmaceutical solid dosage form can be, forexample, 1300-1400 mg.

III. METHODS OF TREATMENT

In one embodiment, the disclosed solid dosage forms can be used fortreating a disease that can be treated by inhibiting HCV RNA polymerase.

In another embodiment, the disclosed solid dosage forms can be used fortreating HCV infection in a subject in need of such treatment. In oneaspect, the subject is suffering from both HCV infection and humanimmunodeficiency virus (HIV) infection.

In another embodiment, the disclosed solid dosage forms can be used fortreating liver disease in a subject in need of such treatment. In oneaspect, the liver disease is end-stage liver disease. In another aspect,the liver disease is cirrhosis. In another aspect, the liver disease ishepatocellular carcinoma. In another aspect, the treatment delays theprogression of the liver disease.

These methods of treatment comprise administering to the subject one ormore of the disclosed solid dosage forms, and, optionally, one or moreadditional therapeutic agents. In one aspect, the method comprisesadministering at least one of the dosage forms once daily to thesubject. In one aspect, the at least one dosage forms administered oncedaily to the subject is a tablet. In another aspect, the methodcomprises administering two of the dosage forms once daily to thesubject. In one aspect, the at least one dosage forms administered oncedaily to the subject are tablets. In another aspect, the methodcomprises administering three of the dosage forms once daily to thesubject. In one aspect, the at least three dosage forms administeredonce daily to the subject are tablets. In another aspect, the dosageforms are administered under non-fasting conditions. In another aspect,the dosage forms are administered under fasting conditions. In anotheraspect, the method comprises administering the two or more dosage formsonce daily at substantially the same time. In another aspect, thesubject in need of treatment is suffering from, or is susceptible to,HCV infection.

IV. COMBINATION THERAPY

The methods of treatment of the present disclosure also comprisecombination therapy in which the disclosed solid dosage forms areco-administered with a second (or even a third, fourth, etc.)composition, such as, for example, a composition containing anothertherapeutic agent used to treat HCV infection (e.g., interferon orinterferon/ribavirin combination, or an HCV inhibitor such as, forexample, an HCV polymerase inhibitor or an HCV protease inhibitor or anNS5a inhibitor). The disclosed solid dosage forms also can beco-administered with therapeutic agents other than therapeutic agentsused to treat HCV infection (e.g., anti-HIV agents). In theseco-administration embodiments, the disclosed solid dosage forms and thesecond, etc. composition(s) may be administered in a substantiallysimultaneous manner (e.g., or within about five minutes of each other),in a sequential manner, or both. It is contemplated that suchcombination therapies may include administering the additionaltherapeutic agent(s) multiple times between the administration of thedisclosed solid dosage forms. The time period between the administrationof each additional therapeutic agent(s) may range from a few seconds (orless) to several hours or days, and will depend on, for example, theproperties of the additional therapeutic agent as formulated (e.g.,potency, solubility, bioavailability, half-life, and kinetic profile),as well as the condition of the patient.

V. KITS

The present disclosure also relates to kits comprising one or more soliddosage forms of the present disclosure. The kit optionally can compriseone or more additional therapeutic agents and/or instructions, forexample, instructions for using the kit. In one embodiment, the kitcomprises a plurality of separate packages with each package containinga daily dose of the solid dosage forms (e.g., a package containing twoor three of the solid dosage forms).

VI. METHODS OF PREPARATION

The present disclosure also relates to methods for preparing the soliddosage forms described in this specification, including those methodsdescribed in the Examples below.

In one embodiment, the disclosure relates to methods for preparing asingle amorphous solid dispersion comprising Compounds 1, 2 and 3 thatcan be used to in the preparation of the dosage form. The amorphoussolid dispersion can be prepared by a variety of techniques such as,without limitation, melt-extrusion, spray-drying, co-precipitation,freeze drying, or other solvent evaporation techniques, withmelt-extrusion and spray-drying being preferred.

In another embodiment, the method generally comprises, for example: (1)preparing a melt comprising Compound 1, Compound 2, Compound 3, apharmaceutically acceptable hydrophilic polymer, and a pharmaceuticallyacceptable surfactant; and (2) solidifying the melt. The solidified meltcan comprise any amorphous solid dispersion described or contemplatedherein. The method can further comprise milling the solidified melt,followed by compressing the milled product with one or more otherexcipients or ingredients to form a tablet core. These other excipientsor ingredients can include, for example, coloring agents, flavoringagents, lubricants or preservatives. In one aspect, the melt is formedat a temperature from 150° C. to 180° C. In another aspect, the melt isformed at a temperature from 150° C. to 170° C. In another aspect, themelt is formed at a temperature from 150° C. to 160° C. In anotheraspect, the melt is formed at a temperature from 160° C. to 170° C.

The melt-extrusion process typically comprises the steps of preparing amelt which includes the active ingredients (i.e., Compound 1, Compound2, and Compound 3), the hydrophilic polymer(s) and optionally thesurfactant(s), and then cooling the melt until it solidifies. “Melting”means a transition into a liquid or rubbery state in which it ispossible for one component to get embedded, such as homogeneouslyembedded, in the other component or components. In many cases, thepolymer component(s) will melt and the other components including theactive ingredients and surfactant(s) will dissolve in the melt therebyforming a solution. Melting usually involves heating above the softeningpoint of the polymer(s). The preparation of the melt can take place in avariety of ways. The mixing of the components can take place before,during or after the formation of the melt. For example, the componentscan be mixed first and then melted or be simultaneously mixed andmelted. The melt can also be homogenized in order to disperse the activeingredients efficiently. In addition, it may be convenient first to meltthe polymer(s) and then to mix in and homogenize the active ingredients.In one example, all materials except surfactant(s) are blended and fedinto an extruder, while the surfactant(s) is molten externally andpumped in during extrusion.

In the melt-extrusion process, the active ingredients can be employed intheir solid forms, such as their respective crystalline forms. Theactive ingredients can also be employed as a solution or dispersion in asuitable liquid solvent such as alcohols, aliphatic hydrocarbons, estersor, in some cases, liquid carbon dioxide. The solvent can be removed,e.g. evaporated, upon preparation of the melt.

Various additives can also be included in the melt, for example, flowregulators (e.g., colloidal silica), binders, lubricants, fillers,disintegrants, plasticizers, colorants, or stabilizers (e.g.,antioxidants, light stabilizers, radical scavengers, and stabilizersagainst microbial attack).

The melting and/or mixing can take place in an apparatus customary forthis purpose such as extruders or kneaders. Suitable extruders mayinclude single screw extruders, intermeshing screw extruders ormulti-screw extruders, such as twin screw extruders, which can beco-rotating or counter-rotating and, optionally, be equipped withkneading disks. It will be appreciated that the working temperatureswill be determined by the kind of extruder or the kind of configurationwithin the extruder that is used. Friction and shearing of the materialin the extruder may provide a substantial amount of energy to themixture and aid in the formation of a homogeneous melt of thecomponents. However, part of the energy needed to melt, mix and dissolvethe components in the extruder can be provided by heating elements.

The consistency of the melt can range from thin to pasty to viscous.Shaping of the extrudate can be conveniently carried out by a calenderwith two counter-rotating rollers with mutually matching depressions ontheir surface. The extrudate can be cooled and allowed to solidify. Theextrudate can also be cut into pieces, either before solidification(hot-cut) or after solidification (cold-cut).

The solidified extrusion product can be further milled, ground orotherwise reduced to granules. The solidified extrudate, as well as eachgranule produced, comprises a solid dispersion, such as a solidsolution, of the active ingredients in a matrix comprised of thehydrophilic polymer(s) and the pharmaceutically acceptablesurfactant(s). The extrusion product can also be blended with otheractive ingredient(s) and/or additive(s) before being milled or groundinto granules. The granules can be further processed into suitable solidoral dosage forms.

In one example, copovidone and one or more surfactants (e.g., vitamin ETPGS in combination with propylene glycol monolaurate) are mixed andgranulated, followed by the addition of aerosil and Compound 1, Compound2, and Compound 3. The mixture is milled, and then subjected toextrusion. The extrudate thus produced can be milled and sieved forfurther processing to make capsules or tablets. Surfactant(s) employedin this example can be added, for example, through liquid dosing duringextrusion.

Alternatively, the amorphous solid dispersion can be prepared using theapproach of solvent evaporation, via spray-drying, which provides theadvantage of allowing for processing at lower temperatures, if needed,and also allows for other modifications to the process in order tofurther improve powder properties. The spray-dried powder can then beformulated further, if needed, and final drug product is flexible withregards to whether capsule, tablet or any other solid dosage form isdesired.

Exemplary spray-drying processes and spray-drying equipment aredescribed in K. Masters, SPRAY DRYING HANDBOOK (Halstead Press, NewYork, 4^(th) ed., 1985). Non-limiting examples of spray-drying devicesthat are suitable for the present invention include spray dryersmanufactured by Niro Inc. or GEA Process Engineering Inc., BuchiLabortechnik AG, and Spray Drying Systems, Inc. A spray-drying processgenerally involves breaking up a liquid mixture into small droplets andrapidly removing solvent from the droplets in a container (spray dryingapparatus) where there is a strong driving force for evaporation ofsolvent from the droplets. Atomization techniques include, for example,two-fluid or pressure nozzles, or rotary atomizers. The strong drivingforce for solvent evaporation can be provided, for example, bymaintaining the partial pressure of solvent in the spray dryingapparatus well below the vapor pressure of the solvent at thetemperatures of the drying droplets. This may be accomplished by either(1) maintaining the pressure in the spray drying apparatus at a partialvacuum; (2) mixing the liquid droplets with a warm drying gas (e.g.,heated nitrogen); or (3) both.

The temperature and flow rate of the drying gas, as well as the spraydryer design, can be selected so that the droplets are dry enough by thetime they reach the wall of the apparatus to be essentially solid and toform a fine powder to avoid sticking to the apparatus wall. Thespray-dried product can be collected by removing the material manually,pneumatically, mechanically or by other suitable means. The actuallength of time to achieve the desired level of dryness depends on thesize of the droplets, the formulation, and spray dryer operation.Following the solidification, the solid powder may stay in the spraydrying chamber for additional time (e.g., 5 seconds to 60 seconds) tofurther evaporate solvent from the solid powder. The final solventcontent in the solid dispersion as it exits the dryer is generally at asufficiently low level so as to improve the stability of the finalproduct. For instance, the residual solvent content of the spray-driedpowder can be less than 2% by weight. The residual solvent content maybe within the limits set forth in the International Conference onHarmonization (ICH) Guidelines. In addition, it may be useful to subjectthe spray-dried composition to further drying to lower the residualsolvent to even lower levels. Methods to further lower solvent levelsinclude, but are not limited to, fluid bed drying, infra-red drying,tumble drying, vacuum drying, and combinations of these and othersuitable processes.

Like the solid extrudate described above, the spray dried productcontains a solid dispersion, such as a solid solution, of the activeingredients in a matrix comprised of the hydrophilic polymer(s) and thepharmaceutically acceptable surfactant(s).

Before feeding into a spray dryer, the active ingredients, thehydrophilic polymer(s), as well as other excipients such as thepharmaceutically acceptable surfactant(s), can be dissolved in asolvent. Suitable solvents include, but are not limited to, alkanols(e.g., methanol, ethanol, 1-propanol, 2-propanol or mixtures thereof),acetone, acetone/water, alkanol/water mixtures (e.g., ethanol/watermixtures), or combinations thereof. The solution can also be preheatedbefore being fed into the spray dryer.

The solid dispersion produced by melt-extrusion, spray-drying or othertechniques can be prepared into any suitable solid oral dosage forms. Inone embodiment, the solid dispersion prepared by melt-extrusion,spray-drying or other techniques (e.g., the extrudate or the spray-driedpowder) can be compressed into tablets. The solid dispersion can beeither directly compressed, or milled or ground into granules or powdersbefore compression. Compression can be performed in a tablet press, suchas in a steel die between two moving punches.

At least one additive selected from flow regulators, binders,lubricants, fillers, disintegrants, or plasticizers may be used incompressing the solid dispersion. These additives can be mixed withground or milled solid dispersion before compacting. Disintegrantspromote a rapid disintegration of the compact in the stomach and keepsthe liberated granules separate from one another. Non-limiting examplesof suitable disintegrants are cross-linked polymers such as cross-linkedpolyvinyl pyrrolidone, cross-linked sodium carboxymethylcellulose orsodium croscarmellose. Non-limiting examples of suitable fillers (alsoreferred to as bulking agents) are lactose monohydrate, calciumhydrogenphosphate, microcrystalline cellulose (e.g., Avicell), silicates(such as silicium dioxide), magnesium oxide, talc, potato or cornstarch, isomalt, or polyvinyl alcohol. Non-limiting examples of suitableflow regulators include highly dispersed silica (e.g., colloidal silicasuch as Aerosil), and animal or vegetable fats or waxes. Non-limitingexamples of suitable lubricants include polyethylene glycol (e.g.,having a molecular weight of from 1000 to 6000), magnesium and calciumstearates, sodium stearyl fumarate, and the like.

Various other additives or ingredients may also be used in preparing asolid composition of the present invention, for example dyes such as azodyes, organic or inorganic pigments such as aluminium oxide or titaniumdioxide, or dyes of natural origin; stabilizers such as antioxidants,light stabilizers, radical scavengers, stabilizers against microbialattack; or other active pharmaceutical ingredients.

Accordingly, one representative embodiment relates to a method of makingthe dosage forms described in this specification, wherein the methodcomprises:

-   -   (a) preparing a melt comprising Compound 1, Compound 2, Compound        3, a hydrophilic polymer, and a surfactant;    -   (b) solidifying the melt to form an amorphous solid dispersion;    -   (c) preparing a first composition comprising the amorphous solid        dispersion;    -   (d) preparing a second composition comprising Compound 4; and    -   (e) formulating the first composition and the second composition        to provide the dosage form.        In one aspect, the preparing the first composition step further        comprises: (a) milling the solidified melt to provide particles        of the amorphous solid dispersion; and (b) optionally combining        the particles of the amorphous solid dispersion with one or more        excipients to provide the first composition. In another aspect,        the melt is prepared at a temperature of 150° C. to 170° C. In        another aspect, the melt is prepared at a temperature of 160° C.        to 170° C.

Another representative embodiment relates to a method of making thedosage forms described in this specification, wherein the methodcomprises:

-   -   (a) preparing the first composition comprising Compound 1,        Compound 2, and Compound 3;    -   (b) granulating (i) a mixture comprising at least a portion of        the Compound 4 with at least a portion of the stabilizing        polymer, or combination of stabilizing polymers, to provide        granules comprising Compound 4; (ii) a mixture comprising at        least a portion of the Compound 4 with at least a portion of the        release rate-modifying polymer, or combination of release        rate-modifying polymers, to provide granules comprising Compound        4; or (iii) a mixture comprising at least a portion of the        Compound 4 with at least a portion of the stabilizing polymer,        or combination of stabilizing polymers, and at least a portion        of the release rate-modifying polymer, or combination of        stabilizing polymers, to provide granules comprising Compound 4;    -   (c) preparing the second composition using the granules as a        source of at least a portion of the Compound 4 present in the        second composition; and    -   (d) formulating the first composition and the second composition        to provide the dosage form.

VII. PRODUCT-BY-PROCESS

The present disclosure also relates to solid dosage forms prepared inaccordance with any of the methods described in this specification,including the methods described in the Examples below.

In one embodiment, the dosage form is prepared by a process comprising:

-   -   granulating (i) a mixture comprising at least a portion of the        Compound 4 with at least a portion of the stabilizing polymer,        or combination of stabilizing polymers, to provide granules        comprising Compound 4; (ii) a mixture comprising at least a        portion of the Compound 4 with at least a portion of the release        rate-modifying polymer, or combination of release rate-modifying        polymers, to provide granules comprising Compound 4; or (iii) a        mixture comprising at least a portion of the Compound 4 with at        least a portion of the stabilizing polymer, or combination of        stabilizing polymers, and at least a portion of the release        rate-modifying polymer, or combination of stabilizing polymers,        to provide granules comprising Compound 4; and    -   preparing the second composition using the granules as a source        of at least a portion of the Compound 4 present in the second        composition.

VIII. EXAMPLES

Unless otherwise stated, in the formulations described in the Examplesbelow: (i) the Compound 1 free acid was used; (ii) the Compound 2 freebase was used; (iii) the Compound 3 free base was used; and the Compound4 monosodium salt monohydrate was used.

Example 1 Bilayer Tablet (Formulation C5-12)

Bilayer tablets (Formulation C5-12) comprising a first bilayer blendcontaining Compound 1, Compound 2, and Compound 3, and a second bilayercontaining Compound 4 were prepared. The specific composition of theresulting Formulation C5-12 is set forth in Table 1-A below.

TABLE 1-A Bilayer Tablet (Formulation C5-12) FORMU- LATION C5-12 (mg/COMPONENT FUNCTION TABLET) BILAYER 1 Compound 1 Mono-Extrudate Compound1 Drug Substance 50.00 Copovidone Polymer Carrier 256.67 Vitamin E, TPGSSurfactant/Plasticizer 16.67 Lauroglycol FCC Surfactant/Plasticizer 6.67Colloidal Silicon Dioxide Glidant 3.33 Compound 2 Mono-ExtrudateCompound 2 Drug Substance 8.33 Copovidone Polymer Carrier 144.9 VitaminE, TPGS Surfactant/Plasticizer 11.67 Colloidal Silicon Dioxide Glidant1.67 Compound 3 Mono-Extrudate Compound 3 Drug Substance 33.33Copovidone Polymer Carrier 164.44 Sorbitan MonolaurateSurfactant/Plasticizer 22.22 Colloidal Silicon Dioxide Glidant 2.22Colloidal Silicon Dioxide Glidant 1.8 Total Bilayer 1 Weight 723.9BILAYER 2 (200 mg Compound 4) Compound 4 granules: Drug Substance 216.2¹Compound 4 (55.7%) (Compound 4) Copovidone Type K 28 (44.3%) Polymer(Copovidone) 172.0 Hypromellose 2208, USP/EP, Polymer 173.2 20,700 mPa ·S (Premium CR) Colloidal Silicon Dioxide Glidant 1.44 MagnesiumStearate, NF/EP, Lubricant 14.46 Impalpable Powder (Veget. Grade) TotalBilayer 2 Weight 577.3 TABLET WEIGHT(mg) 1301.2 ¹Equivalent to 200.0 mgof Compound 4 (free acid).

Each of the Compound 1, Compound 2, and Compound 3 components wasprepared as a separate amorphous solid dispersion comprising the activeingredient using hot melt extrusion technology and milled prior toblending with the other two amorphous solid dispersions. The Compound 1mono-extrudate and the Compound 3 mono-extrudate were prepared asdescribed in Example 4 of published U.S. application US2011/0312973. TheCompound 2 mono-extrudate was prepared as described in Example 1 ofpublished international application WO2011/156578.

A. Compound 1 Mono-Extrudate

As stated above, the Compound 1 mono-extrudate was prepared using hotmelt extrusion technology in which Compound 1 was converted fromcrystalline to amorphous form and uniformly distributed in apolymer-surfactant matrix. The Compound 1 mono-extrudate preparedcontained: (i) copovidone as a carrier polymer, (ii) colloidal silicondioxide as a glidant to aid in powder flow into the extruder, and (iii)vitamin E tocopheryl polyethylene glycol succinate (vitamin E TPGS) andpropylene glycol monolaurate, type I (Lauroglycol™ FCC) assurfactants/plasticizers. The specific composition of the Compound 1mono-extrudate prepared is set forth below in Table 1-B.

TABLE 1-B Compound 1 Mono-Extrudate COMPONENT FUNCTION WEIGHT PERCENTCompound 1 Drug Substance 15¹  Copovidone Polymer Carrier 77  Vitamin E,TPGS Surfactant/Plasticizer 5 Lauroglycol FCC Surfactant/Plasticizer 2Colloidal Silicon Dioxide Glidant 1 ¹Weight/weight % based on free acidequivalent amount of Compound 1.

B. Compound 2 Mono-Extrudate

As stated above, the Compound 2 mono-extrudate was prepared using hotmelt extrusion technology in which Compound 2 was converted fromcrystalline to amorphous form and uniformly distributed in apolymer-surfactant matrix. The Compound 2 mono-extrudate contains: (i)copovidone as a carrier polymer, (ii) colloidal silicon dioxide as aglidant to aid in powder flow into the extruder, and (iii) vitamin Etocopheryl polyethylene glycol succinate (vitamin E TPGS) as asurfactant/plasticizer. The specific composition of the Compound 2mono-extrudate prepared is set forth below in Table 1-C.

TABLE 1-C Compound 2 Mono-Extrudate COMPONENT FUNCTION WEIGHT PERCENTCompound 2 Drug Substance  5¹ Copovidone Polymer Carrier 87  Vitamin E,TPGS Surfactant/Plasticizer 7 Colloidal Silicon Dioxide Glidant 1¹Weight/weight % based on free base equivalent amount of Compound 2.

C. Compound 3 Mono-Extrudate

As stated above, the Compound 3 mono-extrudate was prepared using hotmelt extrusion technology in which Compound 3 was converted fromcrystalline to amorphous form and uniformly distributed in apolymer-surfactant matrix. The Compound 3 mono-extrudate preparedcontained: (i) copovidone as a carrier polymer, (ii) colloidal silicondioxide as a glidant to aid in powder flow into the extruder, and (iii)sorbitan monolaurate as a surfactant/plasticizer. The specificcomposition of the Compound 3 mono-extrudate prepared is set forth belowin Table 1-D.

TABLE 1-D Compound 3 Mono-Extrudate COMPONENT FUNCTION WEIGHT PERCENTCompound 3 Drug Substance  15¹ Copovidone Polymer Carrier 74 SorbitanMonolaurate Surfactant/Plasticizer 10 Colloidal Silicon Dioxide Glidant 1 ¹Weight/weight % based on free acid equivalent amount of Compound 3.

D. First Bilayer Blend

A first bilayer blend comprising the Compound 1 mono-extrudate, theCompound 2 mono-extrudate, and the Compound 3 mono-extrudate wasprepared. The mono-extrudates were each milled, combined in a 46:23:31ratio (Compound 1:Compound 2:Compound 3) based on the weight percent ofactive ingredient, and blended with additional colloidal silicon dioxideto form the first bilayer blend having the composition reported in Table1-E below.

TABLE 1-E First Bilayer Blend (Formulation C5-12) COMPONENT AMOUNT(mg/TABLET) Compound 1 Mono-Extrudate 333.3 Compound 2 Mono-Extrudate166.7 Compound 3 Mono-Extrudate 222.2 Colloidal Silicon Dioxide, NF/EP1.8 TOTAL 724.0

E. Compound 4 Granules

Compound 4 was granulated with copovidone in a fluid bed granulationprocess. Compound 4 was added together with copovidone to the fluid bedgranulator. The powders were fluidized with heated air at approximately35° C. to 55° C. and water was subsequently sprayed from the top ontothe fluidized powder bed. The water was sprayed at a rate sufficient toincrease the moisture content of the granulation to a target ofapproximately 8% to 14% moisture. The water spray rate was then slightlyreduced to maintain the granulation at the target moisture content for ahold period of approximately 15 minutes or longer. The spraying wassubsequently stopped. The heated air temperature was increased and thegranulation was dried until the moisture content was reduced to nogreater than about 2 w/w %. The D₅₀ particle size distribution of thegranules was between 80 and 130 microns. This method of granulationimproved the bulk handling properties of the resulting combination ofCompound 4 and copovidone while maintaining the intrinsic small particlesize of Compound 4. The resulting Compound 4 granules had thecomposition reported in Table 1-F below.

TABLE 1-F Compound 4 Granules (Formulation C5-12) COMPONENT WEIGHTPERCENT Compound 4 (monosodium salt monohydrate) 55.7 Copovidone Type K28 44.3 Purified Water — TOTAL 100

The Compound 4 granules prepared as described above were then blendedwith HPMC Hypromellose 2208, colloidal silicon dioxide, and magnesiumstearate to form the second bilayer blend used in the preparation ofFormulation C5-12. The specific composition of the second bilayer blendis set forth in Table 1-G below.

TABLE 1-G Second Bilayer Blend (Formulation C5-12) BlLAYER 2 (200 mgCompound 4) Compound 4 granules: Compound 4 216.2¹ Compound 4 (55.7%)Copovidone) 172.0 Copovidone Type K 28 (44.3%) Hypromellose 2208,USP/EP, 20,700 173.2 mPa · S (Premium CR) Colloidal Silicon Dioxide 1.44Magnesium Stearate, NF/EP, 14.46 Impalpable Powder (Veget. Grade) Total577.3 ¹Equivalent to 200.0 mg of Compound 4 (free acid).

F. Tablet Preparation (Formulation C5-12)

Formulation C5-12 was prepared by loading a unit dose of the secondbilayer blend into the tablet die (oval, concave tooling, 10 mmwidth×18.8 mm length) on an automated bilayer tablet press, compressingthe second bilayer blend with a compression force of approximately 4 kN,loading a unit dose of the first bilayer blend into the same tablet dieon top of the previously compressed second bilayer blend, andcompressing the first bilayer blend with a compression force ofapproximately 25 kN.

Example 2 Sink Conditions Dissolution Testing

The release profiles of Formulation C5-12 of Example 1 were evaluated ina Sink Conditions dissolution study. The study was conducted in 900 mLof dissolution medium using a standard USP dissolution Apparatus 2(paddle) operating at 100 RPM at 37±0.5° C. The dissolution medium was a0.05 M sodium phosphate buffer pH 6.8 with 15 mM cTAB as a surfactant.

Results for the Compound 1 component of Formulation C5-12 of Example 1are reported in Table 2-A below.

Results for the Compound 2 component of Formulation C5-12 of Example 1are reported in Table 2-B below.

Results for the Compound 3 component of Formulation C5-12 of Example 1are reported in Table 2-C below.

Results for the Compound 4 component of Formulation C5-12 of Example 1are reported in Table 2-D (% Released) and Table 2-E (mg Released)below.

TABLE 2-A Sink Conditions Dissolution Release Profile (Compound 1) Time(Hours) 1 4 6 8 12 16 % Released 54 98 99 102 102 101 Std. Dev. (N = 6)3.2 2.1 2.3 2.4 2.2 2.2

TABLE 2-B Sink Conditions Dissolution Release Profile (Compound 2) Time(Hours) 1 4 6 8 12 16 % Released 55 98 99 103 102 102 Std. Dev. (N = 6)2.8 1.8 1.9 2.1 2.2 2.1

TABLE 2-C Sink Conditions Dissolution Release Profile (Compound 3) Time(Hours) 1 4 6 8 12 16 % Released 58 99 100 103 102 100 Std. Dev. (N = 6)2.9 2.1 1.9 2.2 2.2 2.0

TABLE 2-D Sink Conditions Dissolution Release Profile (Compound 4:Percent Released) Time (Hours) 1 4 6 8 12 16 24 30 % Released 1 11 18 2539 51 70 81 Std. Dev. (N = 6) 0.1 0.7 1.4 1.9 2.6 3.1 3.8 3.9

TABLE 2-E Sink Conditions Dissolution Release Profile (Compound 4: mgReleased) Time (Hours) 1 4 6 8 12 16 24 30 mg Released 2.3 25.7 42.058.3 91.0 119.0 163.3 189.0 Std. Dev. (N = 6) 0.2 1.6 3.3 4.4 6.1 7.28.9 9.1

Example 3 FeSSIF Dissolution Testing

Release profiles are obtained for Formulation C5-12 of Example 1 using aFed-State Simulated Intestinal Fluid (“FeSSIF”) dissolution protocolunder non-sink conditions. The study is conducted in 450 mL ofdissolution medium using a standard USP dissolution Apparatus 2 (paddle)operating at 75 RPM at 37±0.5° C. The dissolution medium is a 0.04 Msodium phosphate buffer pH 6.8 with 11.2 g/L Phares SIF Original Powder(biorelevant.com, Croydon, Surrey, UK) to simulate FeSSIF conditions.Although the Sink Conditions dissolution method discussed in Example 2provides results that are acceptable for general comparisons of releaseprofiles, that method does not account for the conversion of a Compound4 salt to the insoluble Compound 4 free acid in vivo and the resultingreduction in Compound 4 bioavailability that has been observed in vivo.The FeSSIF dissolution method provides results that more closelycorrelate with the observed in vivo results than the Sink Conditionsdissolution method.

Example 4 Human Pharmacokinetic Study (Formulation C5-12)

A Phase 1, non-fasting, open-label, single-dose, two-arm, three-period,randomized, crossover study was conducted to evaluate thepharmacokinetics of Formulation C5-12 of Example 1 and several otherformulations containing Compounds 1, 2, 3, and 4.

Methodology:

Formulation C5-12 and a second formulation were tested in Arm II of thestudy. Adult male and female subjects (N=30 for combined Arm I and ArmII studies) in general good health were selected to participate in thestudy according to the selection criteria. Subjects meeting theselection criteria were randomly assigned to one of the Regimensequences as shown below in Table 4-A.

TABLE 4-A SEQUENCE NUMBER OF REGIMENS ARM NUMBER SUBJECTS PERIOD 1PERIOD 2 PERIOD 3 II 1 5 A * B 2 5 * B A 3 5 B A * * Second formulation.

Study drug was administered as provided below in Table 4-B.

TABLE 4-B REGI- One Single Tablet (i.e., Compound 4 250 mg immediaterelease MEN A tablet) + Two Triple Tablets (each co-formulated tablet(Refer- contains Compound 1 (75 mg), Compound 2 (12.5 mg), and enceCompound 3 (50 mg)) are administered under non-fasting Regi- conditionsin the morning and one Single Tablet is men) administered undernon-fasting conditions in the evening (Day 1 of each period in Arm I andII). REGI- Three Formulation C5-12 tablets (bi-layer tablet/total doseMEN B of Compound 1 (150 mg)/Compound 2 (25 mg)/Compound 3 (100mg)/Compound 4 (600 mg)) are administered in the morning undernon-fasting conditions (Day 1 of each period in Arm II).

Each study regimen was taken orally with approximately 240 mL of waterapproximately 30 minutes after the start of standardized breakfast.Study regimens were administered orally in the morning on Study Day 1 ofeach period. For Regimen A the evening dose of the Single Tablet wastaken orally with approximately 240 mL of water approximately 30 minutesafter the start of the evening snack. Serial blood samples forpharmacokinetic analysis were collected 72 hours after dosing in eachperiod.

Tables 4-C, 4-D, 4-E, and 4-F below report the Arm II pharmacokineticdata for Formulation C5-12 (separately reported for each of Compounds 1,2, 3, and 4). Table 4-G presents the relative bioavailability and 90%confidence intervals results for the pharmacokinetic data of FormulationC5-12 relative to the reference regimen. The data presented in Tables4-C through 4-G are preliminary data and are subject to database lockand final data verification.

Arm II Pharmacokinetic Data (C5-12):

TABLE 4-C Compound 1 Pharmacokinetic Data (C5-12) GEOMETRIC MEAN(ARITHMETIC MEAN, % CV) (N = 13) REGIMEN A PARAMETER (REFERENCE REGIMENE (UNIT) REGIMEN) (C5-12) C_(max) (ng/mL) 900 (1340, 100) 647 (1050, 96)T_(max) (h) 4.8 (30) 5.7 (47) t_(1/2) (h) 5.2 (16) 5.1 (20) AUC_(t) (ng· h/mL) 4670 (6120, 79) 4310 (5930, 82) AUC_(∞) (ng · h/mL) 4690 (6140,79) 4330 (5950, 81) C₂₄ (ng/mL) 24.3 (27.2, 53) 24.5 (28.2, 60)

TABLE 4-D Compound 2 Pharmacokinetic Data (C5-12) GEOMETRIC MEAN(ARITHMETIC MEAN, % CV) (N = 13) REGIMEN A PARAMETER (REFERENCE REGIMENE (UNIT) REGIMEN) (C5-12) C_(max) (ng/mL) 113 (117, 27) 117 (122, 31)T_(max) (h) 4.5 (25) 5.2 (18) t_(1/2) (h) 26.6 (40) 23.2 (35) AUC_(t)(ng · h/mL) 1450 (1500, 24) 1510 (1560, 25) AUC_(∞) (ng · h/mL) 1640(1700, 28) 1670 (1740, 29) C₂₄ (ng/mL) 17.9 (18.7, 29) 18.7 (19.4, 29)

TABLE 4-E Compound 3 Pharmacokinetic Data (C5-12) GEOMETRIC MEAN(ARITHMETIC MEAN, % CV) (N = 13) REGIMEN A PARAMETER (REFERENCE REGIMENE (UNIT) REGIMEN) (C5-12) C_(max) (ng/mL) 1170 (1330, 57) 1160 (1390,57) T_(max) (h) 4.0 (27) 4.9 (35) t_(1/2) (h) 4.9 (27) 4.2 (26) AUC_(t)(ng · h/mL) 7710 (8630, 51) 8160 (9470, 54) AUC_(∞) (ng · h/mL) 7900(8790, 50) 8270 (9560, 53) C₂₄ (ng/mL) 37.0 (42.6, 55) 38.8 (46.3, 62)

TABLE 4-F Compound 4 Pharmacokinetic Data (C5-12) GEOMETRIC MEAN(ARITHMETIC MEAN, % CV) (N = 13) REGIMEN A PARAMETER (REFERENCE REGIMENE (UNIT) REGIMEN) (C5-12) C_(max) (ng/mL) 1240 (1260, 22) 1350 (1480,46) T_(max) (h) 3.1 (34) 9.7 (39) t_(1/2) (h) 5.5 (9) 6.4 (19) AUC_(t)(ng · h/mL) 18200 (18800, 26) 18400 (20200, 47) AUC_(∞) (ng · h/mL)18400 (18900, 26) 18600 (20300, 47) C₂₄ (ng/mL) 361 (392, 42) 290 (344,64)

TABLE 4-G Relative Bioavailability and 90% Confidence Intervals (C5-12)COM- COM- COM- COM- PARAMETER POUND 1 POUND 2 POUND 3 POUND 4 C_(max)0.714^(a) 1.038 1.001 1.094 (0.482- (0.933- (0.821- (0.856- 1.056)^(b)1.155) 1.220) 1.398) AUC_(inf) 0.919 1.022 1.056 1.012 (0.724- (0.963-(0.935- (0.832- 1.167) 1.084) 1.192) 1.231) ^(a)Point Estimate ^(b)90%Confidence Interval

Arm III Pharmacokinetic Data (C5-12):

After completion of the Arm 11 study, an Arm III study was conducted toevaluate the steady-state pharmacokinetics of Formulation C5-12 in a14-day multiple-dose, single period, randomized design (N=12). ThreeFormulation C5-12 tablets were administered under non-fasting conditionsto subjects for 14 days (Study Days 1 through 14).

Tables 4-H, 4-I, 4-J, and 4-K below report the Arm III pharmacokineticdata for Formulation C5-12 (separately reported for each of Compounds 1,2, 3, and 4). The data presented in Tables 4-H through 4-K arepreliminary data and are subject to database lock and final dataverification.

TABLE 4-H Compound 1 Pharmacokinetic Data (C5-12) GEOMETRIC MEAN(ARITHMETIC PARAMETER MEAN, % CV) (N = 14) (UNIT) DAY 1 DAY 14 RATIOAUC₂₄ (ng · h/mL) 4640 (6070, 64) 10600 (15100, 88) 2.28 C_(max) (ng/mL)651 (991, 77) 1640 (2530, 95) 2.52 C₂₄ (ng/mL) 33.7 (38.3, 56) 33.7(44.9, 103) 1.00 T_(max) (h) 6.7 (41) 5.1 (27) β (1/h) — 0.151 (19)t_(1/2) (h) — 4.6 (19)

TABLE 4-I Compound 2 Pharmacokinetic Data (C5-12) GEOMETRIC MEANPARAMETER (ARITHMETIC MEAN, % CV) (N = 14) (UNIT) DAY 1 DAY 14 RATIOAUC₂₄ (ng · h/mL) 1280 (1320, 26) 1720 (1780, 26) 1.34 C_(max) (ng/mL)123 (127, 28) 135 (141, 34) 1.10 C₂₄ (ng/mL) 23.4 (24.4, 30) 40.2 (41.5,24) 1.72 T_(max) (h) 5.5 (29)    5.6 (18)    β (1/h) — 0.023 (41)    t_(1/2) (h) — 29.8 (43)    

TABLE 4-J Compound 3 Pharmacokinetic Data (C5-12) GEOMETRIC MEANPARAMETER (ARITHMETIC MEAN, % CV) (N = 14) (UNIT) DAY 1 DAY 14 RATIOAUC₂₄ (ng · h/mL) 7230 (7970, 41) 10700 (11200, 29) 1.48 C_(max) (ng/mL) 921 (1030, 44) 1430 (1500, 28) 1.55 C₂₄ (ng/mL) 34.7 (41.1, 53) 40.0(42.3, 36) 1.15 T_(max) (h) 5.4 (38)    4.7 (17)    β (1/h) — 0.174 (23)    t_(1/2) (h) — 4.0 (23)   

TABLE 4-K Compound 4 Pharmacokinetic Data (C5-12) GEOMETRIC MEANPARAMETER (ARITHMETIC MEAN, % CV) (N = 14) (UNIT) DAY 1 DAY 14 RATIOAUC₂₄ (ng · h/mL) 13600 (15500, 50) 12000 (13900, 50) 0.88 C_(max)(ng/mL) 1320 (1480, 44) 1250 (1400, 44) 0.95 C₂₄ (ng/mL) 272 (313, 55)172 (210, 61) 0.63 T_(max) (h) 9.0 (20)    9.4 (19)    β (1/h) — 0.117(22)     t_(1/2) (h) — 5.9 (22)   

Example 5 Human Pharmacokinetic Study (Formulation C5-12)

A Phase 1, non-fasting, open-label, two-arm, four-period, randomized,crossover study was conducted to compare and characterize thepharmacokinetics of (i) Triple Tablet when co-administered with SingleTablet, and (ii) Formulation C5-12 as discussed below. Part 1 was asingle dose, two-treatment, randomized, four period, two sequencereplicated crossover study with 88 subjects. Doses in the four periodswere separated by at least 10 days. Part 2 was a multiple-dose,two-treatment, two period, randomized crossover study with 66 subjects.Dosing in each period was 14 days and doses in the two periods wereseparated by at least 10 days.

Methodology:

Adult male and female subjects in general good health were selected toparticipate in the study according to the selection criteria. Subjectsmeeting the selection criteria were randomly assigned to one of thesequences of Regimens A and B (four sequences for Arm I and twosequences for Arm II) as shown below in Table 5-A.

TABLE 5-A REGIMENS ARM N PERIOD 1 PERIOD 2 PERIOD 3 PERIOD 4 I 44 A B AB 44 B A B A II 33 A B 33 B A

Study drug was administered as provided below in Table 5-B.

TABLE 5-B REGIMEN A Three Film-Coated Formulation C5-12 tablets (totaldose of Compound 1 (Test (150 mg)/Compound 2 (25 mg)/Compound 3 (100mg)/Compound 4 (600 mg)) Regimen) were administered in the morning undernon-fasting conditions on Day 1 of each corresponding period in Arm I,and Days 1 through 14 of each corresponding period in Arm II. REGIMEN BOne Single Tablet (i.e., Compound 4 250 mg immediate release tablet) +(Reference Two Triple Tablets (each co-formulated tablet containsCompound 1 (75 mg), Regimen) Compound 2 (12.5 mg), and Compound 3 (50mg)) are administered under non-fasting conditions in the morning andone Single Tablet is administered under non-fasting conditions in theevening on Day 1 of each corresponding period in Arm I, and Days 1through 14 of each corresponding period in Arm II.

Each study regimen was taken orally with approximately 240 mL of waterapproximately 30 minutes after the start of standardized breakfast.Study regimens were administered orally in the morning on Study Day 1 ofeach period. Serial blood samples for pharmacokinetic analysis werecollected 72 hours after dosing in each period.

Arm I Pharmacokinetic Data (Single Dose Study):

Tables 5-C, 5-D, 5-E, and 5-F below report the Arm I pharmacokineticdata for Formulation C5-12 (separately reported for each of Compounds 1,2, 3, and 4). Table 5-G presents the results of a relativebioavailability and 90% confidence interval analysis of thepharmacokinetic data for Formulation C5-12 relative to the referenceregimen. The data presented in Tables 5-C through 5-G are preliminarydata and are subject to database lock and final data verification by thestatistician.

TABLE 5-C Compound 1 Pharmacokinetic Data (Arm I: C5-12) GEOMETRIC MEAN(ARITHMETIC MEAN, % CV) REGIMEN A REGIMEN B PARAMETER (C5-12) (REFERENCEREGIMEN) (UNIT) (N = 172) N = 171) C_(max) (ng/mL) 618 (996, 97)  935(1360, 82) T_(max) (h) 5.0 (5.8, 32) 5.0 (5.1, 27) t_(1/2) (h) 6.15(1.46)   6.02 (1.36)   AUC_(t) (ng · h/mL) 4460 (6450, 86) 5470 (7170,75) AUC_(∞) (ng · h/mL) 4490 (6480, 85) 5490 (7270, 74)

TABLE 5-D Compound 2 Pharmacokinetic Data (Arm I: C5-12) GEOMETRIC MEAN(ARITHMETIC MEAN, % CV) REGIMEN A REGIMEN B PARAMETER (C5-12) (REFERENCEREGIMEN) (UNIT) (N = 172) N = 171) C_(max) (ng/mL) 124 (133, 33) 131(136, 33) T_(max) (h) 5.0 (5.3, 17) 5.0 (5.1, 15) t_(1/2) (h) 37.9(15.3)   39.2 (14.2)   AUC_(t) (ng · h/mL) 1660 (1770, 32) 1630 (1680,31) AUC_(∞) (ng · h/mL) 1800 (1910, 33) 1760 (1840, 30)

TABLE 5-E Compound 3 Pharmacokinetic Data (Arm I: C5-12) GEOMETRIC MEAN(ARITHMETIC MEAN, % CV) REGIMEN A REGIMEN B PARAMETER (C5-12) (REFERENCEREGIMEN) (UNIT) (N = 172) N = 171) C_(max) (ng/mL) 1130 (1320, 48) 1430(1540, 42) T_(max) (h) 4.0 (4.9, 32) 4.0 (4.5, 23) t_(1/2) (h) 4.52(0.99)   4.47 (0.86)   AUC_(t) (ng · h/mL) 7450 (9140, 61) 8610 (9690,58) AUC_(∞) (ng · h/mL) 8090 (9360, 59) 8750 (9920, 56)

TABLE 5-F Compound 4 Pharmacokinetic Data (Arm I: C5-12) GEOMETRIC MEAN(ARITHMETIC MEAN, % CV) REGIMEN A REGIMEN B PARAMETER (C5-12) (REFERENCEREGIMEN) (UNIT) (N = 172) N = 171) C_(max) (ng/mL) 1060 (1210, 46) 1030(1110, 36) T_(max) (h) 8.0 (8.4, 32) 4.0 (4.2, 28) t_(1/2) (h) 6.91(1.99)   5.80 (1.17)   AUC_(t) (ng · h/mL) 12700 (15200, 54) 14800(15900, 38) AUC_(∞) (ng · h/mL) 12900 (15300, 54) 14900 (16100, 38)

TABLE 5-G Relative Bioavailability and 90% Confidence Intervals (Arm I:C5-12) POINT 90% CONFIDENCE REGIMEN PARAMETER ESTIMATE INTERVAL COMPOUND1 A vs. B C_(max) 0.685 0.625-0.750 0.689 0.091 AUC_(t) 0.8490.790-0.911 AUC_(inf) 0.850 0.792-0.912 COMPOUND 2 A vs. B C_(max) 0.9600.926-0.995 AUC_(t) 1.037 1.011-1.064 AUC₂₄ 1.035 1.009-1.062 COMPOUND 3A vs. B C_(max) 0.821 0.777-0.867 AUC_(t) 0.914 0.880-0.949 AUC₂₄ 0.9230.893-0.953 COMPOUND 4 A vs. B C_(max) 1.032 0.950-1.121 AUC_(t) 0.8590.787-0.936 AUC₂₄ 0.863 0.793-0.939

Arm II Pharmacokinetic Data (Multiple Dose Study):

Tables 5-H, 5-I, 5-J, and 5-K below report the Arm II pharmacokineticdata for Formulation C5-12 (separately reported for each of Compounds 1,2, 3, and 4). Table 5-L presents the results of a relativebioavailability and 90% confidence interval analysis of thepharmacokinetic data for Formulation C5-12 relative to the referenceregimen. The data presented in Tables 5-H through 5-L are preliminarydata and are subject to database lock and final data verification by thestatistician.

TABLE 5-H Compound 1 Pharmacokinetic Data (Arm II: C5-12) GEOMETRIC MEAN(ARITHMETIC MEAN, % CV) (N = 63) PARAMETER REGIMEN A REGIMEN B (UNIT)(C5-12) (REFERENCE REGIMEN) AUC₂₄ (ng · h/mL)  8900 (13500, 96)  9240(13200, 82) C_(max) (ng/mL) 1500 (2290, 86) 1947 (2810, 85) T_(max) (h)5.0 (5.2, 30) 4.0 (4.2, 22) C₂₄ (ng/mL)  34.6 (54.2, 141) 30.4 (38.9,73) β (1/h) 0.129 (0.132, 20) 0.128 (0.130, 17) t_(1/2) (h) 5.2 (20)   5.3 (17)   

TABLE 5-I Compound 2 Pharmacokinetic Data (Arm II: C5-12) GEOMETRIC MEAN(ARITHMETIC MEAN, % CV) (N = 63) PARAMETER REGIMEN A REGIMEN B (UNIT)(C5-12) (REFERENCE REGIMEN) AUC₂₄ (ng · h/mL) 1390 (1470, 34) 1240(1330, 37) C_(max) (ng/mL) 128 (135, 31) 117 (127, 35) T_(max) (h) 5.0(5.0, 11) 5.0 (4.8, 18) C₂₄ (ng/mL) 30.5 (33.5, 46) 26.6 (29.6, 49) β(1/h) 0.019 (0.020, 34) 0.019 (0.020, 34) t_(1/2) (h) 35.1 (34)     35.0(34)    

TABLE 5-J Compound 3 Pharmacokinetic Data (Arm II: C5-12) GEOMETRIC MEAN(ARITHMETIC MEAN, % CV) (N = 63) PARAMETER REGIMEN A REGIMEN B (UNIT)(C5-12) (REFERENCE REGIMEN) AUC₂₄ (ng · h/mL) 8670 (9470, 43) 9580(10700, 50) C_(max) (ng/mL) 1340 (1440, 39) 1680 (1800, 44) T_(max) (h)4.0 (4.6, 21) 4.0 (4.1, 19) C₂₄ (ng/mL) 36.2 (44.3, 76) 35.1 (43.2, 73)β (1/h) 0.147 (0.152, 25) 0.142 (0.145, 23) t_(1/2) (h) 4.6 (25)    4.8(23)   

TABLE 5-K Compound 4 Pharmacokinetic Data (Arm II: C5-12) GEOMETRIC MEAN(ARITHMETIC MEAN, % CV) (N = 63) PARAMETER REGIMEN A REGIMEN B (UNIT)(C5-12) (REFERENCE REGIMEN) AUC₂₄ (ng · h/mL)  8810 (10300, 55)  9770(10600, 42) C_(max) (ng/mL) 799 (896, 46) 879 (932, 40) T_(max) (h) 8.0(8.4, 35) 4.0 (5.2, 79) C₂₄ (ng/mL) 116 (155, 87) 162 (183, 55) β (1/h)0.104 (0.111, 30) 0.122 (0.127, 44) t_(1/2) (h) 6.2 (30)    5.5 (24)   

TABLE 5-L Relative Bioavailability and 90% Confidence Intervals (Arm II:C5-12) POINT 90% CONFIDENCE REGIMEN PARAMETER ESTIMATE INTERVAL COMPOUND1 A vs. B C_(max) 0.727 0.642-0.823 AUC₂₄ 0.903 0.817-0.998 C₂₄ 1.0550.970-1.147 COMPOUND 2 A vs. B C_(max) 1.087 1.006-1.174 AUCt 1.0911.065-1.119 AUC₂₄ 1.098 1.064-1.132 COMPOUND 3 A vs. B C_(max) 0.7930.747-0.843 AUCt 0.894 0.847-0.944 AUC₂₄ 1.009 0.946-1.075 COMPOUND 4 Avs. B C_(max) 0.905 0.823-0.995 AUCt 0.893 0.810-0.986 AUC₂₄ 0.7100.622-0.812

With respect to the observed pharmacokinetics of Formulation C5-12relative to the reference regimen in Arm I of the study:

(1) C_(max) for Compound 1 was lower (by 30%) than C_(max) for thereference regimen. Otherwise, the exposures for Compound 1, Compound 2,Compound 3, and Compound 4 were comparable (less than 20% difference) toexposures from the reference regimen. Based on the exposures-efficacy ofCompound 1, Compound 2, and Compound 3, however, these differences werenot deemed clinically significant.

(2) For the AUC of Compound 4 and Compound 1 and the C_(max) of Compound3, the lower 90% confidence bounds were slightly lower than 0.80 (lessthan 2% difference) and the geometric mean exposures were within 20% ofthe exposures from the reference regimen. These differences were notdeemed clinically significant.

With respect to the observed pharmacokinetics of Formulation C5-12relative to the reference regimen in Arm II of the study:

(1) Compound 1 and Compound 3 exposures (C_(24,ss) and AUC_(24,ss)) werebioequivalent (point estimate and 90% confidence interval for thegeometric mean ratio (“GMR”) within 0.80-1.25) to exposures from thereference regimen except for C_(max,ss), which was lower (by 27% and21%, respectively) than C_(max,ss) for the reference regimen. Based onthe exposures-efficacy, however, the difference in C_(max,ss) was notdeemed clinically significant.

(2) Compound 2 exposures were bioequivalent (point estimate and 90%confidence interval for the GMR within 0.80-1.25) to exposures from thereference regimen.

(3) Compound 4 exposures (C_(max,ss) and AUC_(24,ss)) were bioequivalent(point estimate and 90% confidence interval for the GMR within0.80-1.25) to exposures from the reference regimen except for theC_(24,ss) (C_(trough)) which was lower (by 29%) than the C_(24,ss)(C_(trough)) for the reference regimen. Based on the exposures-efficacy,however, the difference in C_(trough) was not deemed clinicallysignificant.

It should be understood that the above-described embodiments and theexamples are given by way of illustration, not limitation. Variouschanges and modifications within the scope of the present invention willbecome apparent to those skilled in the art from the presentdescription.

All references (patent and non-patent) cited above are incorporated byreference into this patent disclosure. The discussion of thosereferences is intended merely to summarize the assertions made by theirauthors. No admission is made that any reference (or a portion of anyreference) is relevant prior art (or prior art at all). Applicantsreserve the right to challenge the accuracy and pertinence of the citedreferences.

What is claimed is:
 1. A solid dosage form comprising a firstcomposition and a second composition, wherein: the first compositioncomprises from 40 mg to 180 mg of

from 5 mg to 30 mg of

from 25 mg to 120 mg of ritonavir, 70-85% by weight of copovidone; and5% to 10% by weight of a pharmaceutically acceptable surfactant or acombination of pharmaceutically acceptable surfactants, wherein allpercentages are weight percentages relative to the total weight of thefirst composition, and wherein Compound 1, Compound 2 and ritonavir areformulated in an amorphous solid dispersion; the second compositioncomprises from 75 mg to 900 mg (free acid equivalent) of a sodiummonohydrate salt of

20-40% copovidone, and 20-40% hypromellose, wherein all percentages areweight percentages relative to the total weight of the secondcomposition; when dissolved in 900 mL of a dissolution medium using astandard USP dissolution Apparatus 2 (paddle) operating at 100 RPM at37° C., 50-60% Compound 1 in the solid dosage form is released within 1hour, 50-60% Compound 2 in the solid dosage form is released within 1hour, 50-60% ritonavir in the solid dosage form is released within 1hour, and 0.5-2% Compound 4 in the solid dosage form is released within1 hour, wherein the dissolution medium is 0.05 M sodium phosphate buffer(pH 6.8) with 15 mM cetyltrimethylammonium bromide (cTAB), and the totalweight of the solid dosage form is from 100 mg to 1600 mg.
 2. The soliddosage form of claim 1, wherein the first composition comprises from 45mg to 55 mg of Compound 1, from 7.5 mg to 9.5 mg of Compound 2, and from30 mg to 37 mg of ritonavir, and the second composition comprises from150 mg to 300 mg (free acid equivalent) of the sodium monohydrate saltof Compound
 4. 3. A method for treating hepatitis C virus (HCV)infection in a patient in need of such treatment, wherein the methodcomprises administering once daily to the patient at least one soliddosage form of claim
 1. 4. A method for treating HCV infection in apatient in need of such treatment, wherein the method comprisesadministering once daily to the patient three solid dosage forms ofclaim
 1. 5. A solid dosage form comprising a first composition and asecond composition, wherein: the first composition comprises from 40 mgto 180 mg of Compound 1, from 5 mg to 30 mg of Compound 2, from 25 mg to120 mg of ritonavir, 70-85% by weight of copovidone; and 5% to 10% byweight of a pharmaceutically acceptable surfactant or a combination ofpharmaceutically acceptable surfactants, wherein all percentages areweight percentages relative to the total weight of the firstcomposition, and wherein Compound 1, Compound 2 and ritonavir areformulated in an amorphous solid dispersion; the second compositioncomprises from 75 mg to 900 mg (free acid equivalent) of a sodiummonohydrate salt of Compound 4, 20-40% copovidone, and 20-40%hypromellose, wherein all percentages are weight percentages relative tothe total weight of the second composition; when dissolved in 900 mL ofa dissolution medium using a standard USP dissolution Apparatus 2(paddle) operating at 100 RPM at 37° C., 95-100% Compound 1 in the soliddosage form is released within 4 hours, 95-100% Compound 2 in the soliddosage form is released within 4 hours, 95-100% ritonavir in the soliddosage form is released within 4 hours, and 10-15% Compound 4 in thesolid dosage form is released within 4 hours, wherein the dissolutionmedium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB, andthe total weight of the solid dosage form is from 1000 mg to 1600 mg. 6.The solid dosage form of claim 5, wherein the first compositioncomprises from 45 mg to 55 mg of Compound 1, from 7.5 mg to 9.5 mg ofCompound 2, and from 30 mg to 37 mg of ritonavir, and the secondcomposition comprises from 150 mg to 300 mg (free acid equivalent) ofthe sodium monohydrate salt of Compound
 4. 7. A method for treating HCVinfection in a patient in need of such treatment, wherein the methodcomprises administering once daily to the patient at least one soliddosage form of claim
 5. 8. A method for treating HCV infection in apatient in need of such treatment, wherein the method comprisesadministering once daily to the patient three solid dosage forms ofclaim
 5. 9. A solid dosage form comprising a first composition and asecond composition, wherein: the first composition comprises from 40 mgto 180 mg of Compound 1, from 5 mg to 30 mg of Compound 2, from 25 mg to120 mg of ritonavir, 70-85% by weight of copovidone; and 5% to 10% byweight of a pharmaceutically acceptable surfactant or a combination ofpharmaceutically acceptable surfactants, wherein all percentages areweight percentages relative to the total weight of the firstcomposition, and wherein Compound 1, Compound 2 and ritonavir areformulated in an amorphous solid dispersion; the second compositioncomprises from 75 mg to 900 mg (free acid equivalent) of a sodiummonohydrate salt of Compound 4, 20-40% copovidone, and 20-40%hypromellose, wherein all percentages are weight percentages relative tothe total weight of the second composition; when dissolved in 900 mL ofa dissolution medium using a standard USP dissolution Apparatus 2(paddle) operating at 100 RPM at 37° C., 95-100% Compound 1 in the soliddosage form is released within 6 hours, 95-100% Compound 2 in the soliddosage form is released within 6 hours, 95-100% ritonavir in the soliddosage form is released within 6 hours, and 15-20% Compound 4 in thesolid dosage form is released within 6 hours, wherein the dissolutionmedium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB, andthe total weight of the solid dosage form is 1000 mg to 1600 mg.
 10. Thesolid dosage form of claim 9, wherein the first composition comprisesfrom 45 mg to 55 mg of Compound 1, from 7.5 mg to 9.5 mg of Compound 2,and from 30 mg to 37 mg of ritonavir, and the second compositioncomprises from 150 mg to 300 mg (free acid equivalent) of the sodiummonohydrate salt of Compound
 4. 11. A method for treating HCV infectionin a patient in need of such treatment, wherein the method comprisesadministering once daily to the patient at least one solid dosage formof claim
 9. 12. A method for treating HCV infection in a patient in needof such treatment, wherein the method comprises administering once dailyto the patient three solid dosage forms of claim
 9. 13. A solid dosageform comprising a first composition and a second composition, wherein:the first composition comprises from 40 mg to 180 mg of Compound 1, from5 mg to 30 mg of Compound 2, from 25 mg to 120 mg of ritonavir, 70-85%by weight of copovidone; and 5% to 10% by weight of a pharmaceuticallyacceptable surfactant or a combination of pharmaceutically acceptablesurfactants, wherein all percentages are weight percentages relative tothe total weight of the first composition, and wherein Compound 1,Compound 2 and ritonavir are formulated in an amorphous soliddispersion; the second composition comprises from 75 mg to 900 mg (freeacid equivalent) of a sodium monohydrate salt of Compound 4, 20-40%copovidone, and 20-40% hypromellose, wherein all percentages are weightpercentages relative to the total weight of the second composition; whendissolved in 900 mL of a dissolution medium using a standard USPdissolution Apparatus 2 (paddle) operating at 100 RPM at 37° C., 100%Compound 1 in the solid dosage form is released within 8 hours, 100%Compound 2 in the solid dosage form is released within 8 hours, 100%ritonavir in the solid dosage form is released within 8 hours, 20-30%Compound 4 in the solid dosage form is released within 8 hours, 30-40%Compound 4 in the solid dosage form is released within 12 hours, and40-60% Compound 4 in the solid dosage form is released within 16 hours,wherein the dissolution medium is 0.05 M sodium phosphate buffer (pH6.8) with 15 mM cTAB, and the total weight of the solid dosage form isfrom 1000 mg to 1600 mg.
 14. The solid dosage form of claim 13, whereinthe first composition comprises from 45 mg to 55 mg of Compound 1, from7.5 mg to 9.5 mg of Compound 2, and from 30 mg to 37 mg of ritonavir,and the second composition comprises from 150 mg to 300 mg (free acidequivalent) of the sodium monohydrate salt of Compound
 4. 15. A methodfor treating HCV infection in a patient in need of such treatment,wherein the method comprises administering once daily to the patient atleast one solid dosage form of claim
 13. 16. A method for treating HCVinfection in a patient in need of such treatment, wherein the methodcomprises administering once daily to the patient three solid dosageforms of claim
 13. 17. A solid dosage form comprising a firstcomposition and a second composition, wherein: the first compositioncomprises from 40 mg to 180 mg of Compound 1, from 5 mg to 30 mg ofCompound 2, from 25 mg to 120 mg of ritonavir, 70-85% by weight ofcopovidone; and 5% to 10% by weight of a pharmaceutically acceptablesurfactant or a combination of pharmaceutically acceptable surfactants,wherein all percentages are weight percentages relative to the totalweight of the first composition, and wherein Compound 1, Compound 2 andritonavir are formulated in an amorphous solid dispersion; the secondcomposition comprises from 75 mg to 900 mg (free acid equivalent) of asodium monohydrate salt of Compound 4, 20-40% copovidone, and 20-40%hypromellose, wherein all percentages are weight percentages relative tothe total weight of the second composition; when dissolved in 900 mL ofa dissolution medium using a standard USP dissolution Apparatus 2(paddle) operating at 100 RPM at 37° C., 100% Compound 1 in the soliddosage form is released within 8 hours, 100% Compound 2 in the soliddosage form is released within 8 hours, 100% ritonavir in the soliddosage form is released within 8 hours, 20-30% Compound 4 in the soliddosage form is released within 8 hours, 30-40% Compound 4 in the soliddosage form is released within 12 hours, 40-60% Compound 4 in the soliddosage form is released within 16 hours, and 60-80% Compound 4 in thesolid dosage form is released within 24 hours, wherein the dissolutionmedium is 0.05 M sodium phosphate buffer (pH 6.8) with 15 mM cTAB, andthe total weight of the solid dosage form is from 1000 mg to 1600 mg.18. The solid dosage form of claim 17, wherein the first compositioncomprises from 45 mg to 55 mg of Compound 1, from 7.5 mg to 9.5 mg ofCompound 2, and from 30 mg to 37 mg of ritonavir, and the secondcomposition comprises from 150 mg to 300 mg (free acid equivalent) ofthe sodium monohydrate salt of Compound
 4. 19. A method for treating HCVinfection in a patient in need of such treatment, wherein the methodcomprises administering once daily to the patient at least one soliddosage form of claim
 17. 20. A method for treating HCV infection in apatient in need of such treatment, wherein the method comprisesadministering once daily to the patient three solid dosage forms ofclaim 17.